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WO2025029929A1 - Multi-cyclic irak1 and irak4 inhibiting compounds and uses thereof - Google Patents

Multi-cyclic irak1 and irak4 inhibiting compounds and uses thereof Download PDF

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Publication number
WO2025029929A1
WO2025029929A1 PCT/US2024/040403 US2024040403W WO2025029929A1 WO 2025029929 A1 WO2025029929 A1 WO 2025029929A1 US 2024040403 W US2024040403 W US 2024040403W WO 2025029929 A1 WO2025029929 A1 WO 2025029929A1
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subject
compound
inhibitor
expression
irak1
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French (fr)
Inventor
Scott Bryan HOYT
Daniel T. STARCZYNOWSKI
Craig Joseph THOMAS
Jan Susan Rosenbaum
Joshua Bennett
Gregory M. HAYES
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Cincinnati Childrens Hospital Medical Center
US Department of Health and Human Services
Kurome Therapeutics Inc
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Cincinnati Childrens Hospital Medical Center
US Department of Health and Human Services
Kurome Therapeutics Inc
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Publication of WO2025029929A1 publication Critical patent/WO2025029929A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57426—Specifically defined cancers leukemia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • BACKGROUND IRAKs are a family of related kinases that operate at the nexus of multiple innate immune and inflammatory pathways implicated in myeloid malignancies. There is increasing interest in the role of the IRAK kinases as targets in the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) (reviewed in J Bennett and DT Starczynowski, Curr Opin Hematol 2022).
  • IRAK1 and IRAK4 lie downstream of multiple receptors that stimulate the canonical NF-kB signaling pathway upstream of TRAF6 via the myddosome complex. While TRAF6 is necessary to preserve the tonic NF-kB signaling that is required for hematopoietic stem cell (HSC) homeostasis (J Fang et. al. Cell Reports 2018), overactivity of the NF-kB signaling pathway has been implicated in both MDS and AML (reviewed in MCJ Bosman et. al., Crit Rev Oncol/Hematol 2016; JJ Trowbridge and DT Starczynowski, J Exp Med 2021).
  • HSC hematopoietic stem cell
  • MDS and AML exist along a continuous disease spectrum starting with early-stage MDS, which may progress to high-risk (HR) MDS and/or AML.
  • HR high-risk
  • AML is a heterogeneous malignancy characterized by suppression of normal hematopoiesis and overproduction of immature myeloid blast cells associated with a differentiation block.
  • Most patients with HR-MDS and AML are not cured with available therapies, underscoring the urgent need for new therapeutic alternatives that will improve the clinical outcomes of these patients. Despite significant effort, the five-year relative survival of AML patients remains at only 25%.
  • MDS and AML originate in hematopoietic stem and progenitor cells (HSPC, referred to as leukemic stem/progenitor cells [LSPC]) that acquire genetic and/or epigenetic abnormalities.
  • HSPC hematopoietic stem and progenitor cells
  • LSPC leukemic stem/progenitor cells
  • a pool of LSPCs persist throughout the course of disease to replenish the bulk leukemic blast cells and contribute to treatment-related relapse when not eradicated.
  • Recent therapies such as Venetoclax with Azacytidine and Menin inhibitors, that target the LSPCs have shown improved clinical outcomes for patients with HR-MDS and AML.
  • LSPCs also share cellular states and transcriptional programs with normal HSPCs, such as ones that maintain multi-potent self-renewal properties and prevent untimely differentiation.
  • LSPCs Like normal HSPCs, LSPCs have acquired an undifferentiated state that permits long-term expansion of progeny cells, properties which have been evaluated using surrogate in vitro progenitor assays (i.e., colony assays in methylcellulose) and in vivo hematopoietic transplantation models. Uncovering targetable signaling dependencies unique to LSPCs is critical to improve therapeutic responses in patients. It was recently reported that patient-derived LSPCs from HR- MDS and across various AML subtypes exhibit a high frequency of dysregulated immune and inflammatory pathways. Dysregulation of immune-related genes is observed in >50% of MDS and AML, and chronic innate immune pathway activation increases the risk of developing myeloid malignancies.
  • TLR Toll-like receptor
  • IL-1R Interleukin 1 receptor
  • IRAK interleukin-1 receptor associated kinases
  • activation of TLRs or IL-1R leads to recruitment of the adaptor protein MyD88, which then nucleates an oligomeric signaling complex (Myddosome) that includes MyD88 and IRAK4.
  • IRAK4 subsequently recruits and phosphorylates IRAK1 or IRAK2, which then induces multiple downstream effectors, including NF-kB and MAPKs.
  • Chronic activation of this MyD88-IRAK canonical signaling axis is presumed to underly malignant hematopoiesis in MDS/AML, a theory that is partially supported by the discovery of activating mutations in MyD88 that cause spontaneous assembly of the Myddosome complex in lymphomas. Consequently, IRAK4 inhibitors and proteolysis targeting chimeric (PROTAC) small molecule degraders are undergoing evaluation in pre-clinical studies and early phase clinical trials for hematologic malignancies and inflammatory conditions.
  • PROTAC proteolysis targeting chimeric
  • the IRAK4 kinase inhibitor PF-06650833 (Zimlovisertib) is being evaluated for chronic inflammatory disorders, while CA-4948 (Emavusertib) is being evaluated in hematologic malignancies, including lymphoma, HR- and low-risk (LR)-MDS, and refractory/relapsed AML.
  • the IRAK4 PROTACs, KT-474 and KT-413, are being evaluated in immuno-inflammatory disease and MyD88-mutant lymphomas, respectively. Safety data from these trials have revealed minimal on-target toxicity nor adverse effects, suggesting that targeting IRAK4 will have an acceptable safety profile and tolerability.
  • the present disclosure provides a method of treating an inflammatory disease or disorder, or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), in a subject in need thereof, the method comprising administering to the subject Compound 8: or a salt, ester, solvate, optical of an isomer thereof.
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • the inflammatory disease or disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis.
  • the AML is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML
  • the MDS is MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, or MDS with a splicing factor mutation, optionally wherein the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1, SRSF2, SF3B1, or ZRSR2.
  • the subject has AML and the subject has a gene mutation in one or more of FLT3, TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, JAK2, ASXL1, ABL1, ATRX, BCORL1, KDM6A, PTPN11, TP53, CBL, CEBPA, FBXW7, HRAS, NRAS, IDH1, IDH2, NRAS, PDGFRA, SF3B1, ETV6, PHF6, GNAS, KRAS, NOTCH1, STAG2, SETBP1, GATA1, GATA2, WT1, SRSF2, GNAS, CEBPA, CALR, MPL, BCL11A, ATM, CTCF, U2AF1, TYK2, FBX, RUI, RAD21, or MLL3, or the subject has MDS and the subject has a gene mutation in one or more of DB1/ 147901903.2 4 U2
  • Compound 8 has an IRAK1 IC50 of less than about 40 nM, optionally less than about 5 nM, and/or a FLT3 IC50 of less than about 2.5 nM. In one embodiment, Compound 8 has an IRAK4:IRAK1 inhibitory potency ratio of less than about 40. In one embodiment, the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes and/or decreased expression of one or more IRAK1/4-associated genes. In one embodiment, the subject in need thereof has elevated expression and/or decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject.
  • the subject in need thereof has elevated expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19,
  • the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19,
  • Compound 8 upon administration to the subject, decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject, and/or increases the expression of one or more IRAK1/4-associated genes found to be decreased in the subject. In one embodiment, the administration of Compound 8 decreases the expression of the one or more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of the one or more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8.
  • the administration of Compound 8 decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control DB1/ 147901903.2 9 subject, and/or increases the expression of one or more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject.
  • Compound 8 decreases the expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBG
  • Compound 8 upon administration to the subject, increases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP
  • the subject in need thereof has elevated expression of one or more NF ⁇ B- associated genes, and/or decreased expression of one or more NF ⁇ B-associated genes. In one embodiment, the subject in need thereof has elevated expression of one or more NF ⁇ B- associated genes compared to a healthy control subject, and/or decreased expression of one or more NF ⁇ B-associated genes compared to a healthy control subject. In one embodiment, the subject in need thereof has elevated expression of one or more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • the subject in need thereof has decreased expression of one or more NF ⁇ B- DB1/ 147901903.2 15 associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Compound 8 upon administration to the subject, decreases the expression of one or more NF ⁇ B-associated genes found to be elevated in the subject, and/or increases the expression of one or more NF ⁇ B-associated genes found to be decreased in the subject. In one embodiment, the administration of Compound 8 decreases the expression of the one or more NF ⁇ B-associated genes found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of the one or more NF ⁇ B-associated genes found to be decreased in the subject before the administration of Compound 8.
  • Compound 8 decreases the expression of one or more NF ⁇ B-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more NF ⁇ B- associated genes found to be decreased in the subject compared to a healthy control subject. In one embodiment, upon administration to the subject, Compound 8 decreases the expression of one or more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Compound 8 upon administration to the subject, increases the expression of one or DB1/ 147901903.2 18 more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • the subject in need thereof has elevated secretion of one or more cytokines, optionally wherein the one or more cytokines are selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN- ⁇ .
  • the one or more cytokines are selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN- ⁇ .
  • Compound 8 decreases the secretion of one or more cytokines found to be elevated in the subject, optionally wherein the compound decreases the secretion of one or more cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM- CSF, and IFN- ⁇ in the subject.
  • the administration of Compound 8 decreases the expression of the one or more cytokines found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of the one or more cytokines found to be decreased in the subject before the administration of Compound 8.
  • Compound 8 DB1/ 147901903.2 20 provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject, optionally wherein the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1.
  • the administration of Compound 8 comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration; and/or Compound 8 is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight; and/or Compound 8 is administered to the subject in a dosage of from about 0.35 mg to about 70,000 mg; and/or Compound 8 is administered to the subject daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once a week, twice a month, or once a month.
  • Compound 8 treats the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject during the time period that the compound is administered to the subject. In one embodiment, in any of the methods described above, Compound 8 continues to treat the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject after the administration is stopped, optionally wherein Compound 8 continues to treat the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped.
  • the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof; and/or the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, or acalabrutinib or a pharmaceutically acceptable salt thereof; and/or the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof; and/or the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof; and/or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of determining whether a subject with a disease or disorder selected from an inflammatory disease or disorder, and a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), can be treated by administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, the method comprising: determining whether the subject has an elevated expression of one or more IRAK1/4-associated genes and/or a decreased expression of one or more IRAK1/4-associated genes, wherein the IRAK1/4-associated genes are selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP
  • the subject has elevated expression of one or more IRAK1/4-associated genes compared to a healthy control subject and/or a decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject.
  • the subject in need thereof has an elevated expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM
  • the subject in need thereof has a decreased expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD
  • Compound 8 decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject, and/or increases the expression of one or more IRAK1/4- associated genes found to be decreased in the subject. In one embodiment, Compound 8 decreases the expression of the one or more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of the one DB1/ 147901903.2 29 or more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8.
  • Compound 8 decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject.
  • Compound 8 decreases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SP
  • Compound 8 increases the expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE
  • the subject has elevated expression of one or more NF ⁇ B-associated genes compared to a healthy control subject and/or a decreased expression of one or more IRAK1/4- associated genes compared to a healthy control subject.
  • subject in need thereof has an elevated expression of one or more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL
  • the subject in need thereof has a decreased expression of one or more NF ⁇ B- associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • Compound 8 decreases the expression of one or more NF ⁇ B-associated genes found to be elevated in the subject, and/or increases the expression of one or more NF ⁇ B- associated genes found to be decreased in the subject. In one embodiment, Compound 8 decreases the expression of one or more NF ⁇ B-associated genes found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of one or more DB1/ 147901903.2 38 NF ⁇ B-associated genes found to be decreased in the subject before the administration of Compound 8.
  • Compound 8 decreases the expression of one or more NF ⁇ B- associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more NF ⁇ B-associated genes found to be decreased in the subject compared to a healthy control subject. In one embodiment, Compound 8 decreases the expression of one or more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Compound 8 increases the expression of one or more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, DB1/ 147901903.2 40 GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11
  • the present disclosure provides a method of determining whether a subject with a disease or disorder selected from an inflammatory disease or disorder, or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), can be treated by the administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, the method comprising: determining whether the subject has DB1/ 147901903.2 41 an elevated secretion of one or more cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN- ⁇ .
  • cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM
  • the subject has elevated expression of one or more cytokines compared to a healthy control subject and/or a decreased expression of one or more cytokines compared to a healthy control subject.
  • any of the methods described above further comprise administering to the subject Compound 8: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • the inflammatory disease or disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis.
  • the AML is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML, optionally wherein the subject has AML and the subject has a gene mutation in one or more of FLT3, TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, JAK2, ASXL1, ABL1, ATRX, BCORL1, KDM6A, PTPN11, TP53, CBL, CEBPA, FBXW7, HRAS, NRAS, IDH1, IDH2, NRAS, PDGFRA, SF3B1, ETV6, PHF6, GNAS, KRAS, NOTCH1, STAG2, SETBP1, GATA1, G
  • Compound 8 has an IRAK1 IC 50 of less than about 40 nM, optionally an IRAK4 IC50 of less than about 5 nM, and/or an FLT3 IC50 of less than about 2.5 nM. In one embodiment, Compound 8 has IRAK4:IRAK1 inhibitory potency ratio of less than about 40. In one embodiment, Compound 8 is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1.
  • Compound 8 provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject, optionally wherein the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1.
  • the administration of Compound 8 comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration; and/or Compound 8 is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight; and/or Compound 8 is administered to the subject in a dosage of from about 0.35 mg to about 70,000 mg; and/or Compound 8 is administered to the subject daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once a week, twice a month, or once a month.
  • Compound 8 treats the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject during the time period that the compound is administered to the subject. In one embodiment, in any of the methods described above, Compound 8 continues to treat the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject after the administration is stopped, optionally Compound 8 continues to treat the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped.
  • the method further comprises administering to the subject one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a DB1/ 147901903.2 43 BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a
  • the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof; and/or the BTK inhibitor is ibrutinib or acalabrutinib or a pharmaceutically acceptable salt of any one thereof; and/or the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof; and/or the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof; and/or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
  • the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof increases survival of the subject; optionally the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof; DB1/ 147901903.2 44 optionally wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%,
  • FIG.1 depicts that the NFkB potency of Compounds 1-13, Compound 15, and comparative compounds correlates with their IRAK1 potency.
  • FIG.2 depicts that the NFkB potency of Compounds 1-13, Compound 15, and comparative compounds correlates with their IRAK4 potency.
  • FIG.3 depicts colony forming assays demonstrating that the NFkB potency of Compounds 1-13 and Compound 15 correlates with their MDSL CFC potency.
  • FIG.4 depicts colony forming assays demonstrating that the NFkB potency of Compounds 1-13 and Compound 15 correlates with their THP-1 CFC potency.
  • FIG.5 depicts the kinase profile of comparative compounds with their PAM and IL1 ⁇ IC50.
  • FIG.6A depicts Compound 14 and Compound 15.
  • FIG.6B depicts the kinase profile of Compound 14 and Compound 15 with their PAM and IL1 ⁇ IC 50 .
  • FIG.7 depicts the kinase profile of Compound 2, Compound 7, and Compound 8 with their PAM and IL1 ⁇ IC 50 .
  • FIGS.8A-8B depict the MS methods used in Example 2. The MS is the standard curve quantitation values demonstrating the range of quants applicable from the qualified assay using recombinant proteins assessed via the method.
  • FIG.8A depicts IRAK1/4 expression analysis by IP-MS.
  • FIG.8B depicts hybrid LCMS.
  • FIG.9 demonstrates that Compound 8 is a highly potent and selective IRAK1/IRAK4/panFLT3 inhibitor.
  • FIG.10 demonstrates that dual IRAK1/4 inhibition drives NF- ⁇ B signaling, wherein complete antagonism of signaling through both receptor pathways is only seen with the IRAK1/4 inhibitor Compound 8.
  • FIGS.11A-11C demonstrate that Compound 8 suppresses NF- ⁇ B and IRAK1/4- dependent signaling in AML cells.
  • FIG.11A is a principal component analysis (PCA) plot showing the variation between the samples in THP-1 cells.
  • PCA principal component analysis
  • FIG.11B is a plot depicting the relative expression of NF- ⁇ B target genes by their Z-score (blue downregulated genes, red upregulated genes).
  • FIG.11C is a plot depicting the relative expression of IRAK1/4 dependency genes by their Z-score (blue downregulated genes, red upregulated genes).
  • FIG.12 is a chart depicting differentially expressed genes (DEGs) for different concentrations of Compound 8 and CA-4948 (emavusertib) calculated by comparison against control samples.
  • FIGS.13A-13C are charts of DEGs versus drug concentration.
  • FIG.13A is a chart of control versus 1 ⁇ M Compound 8 DEGs.
  • FIG.13B is a chart of control versus 5 ⁇ M Compound 8 DEGs.
  • FIG 13C is a chart of control versus 10 ⁇ M CA-4948 DEGs.
  • FIGS.14A-14C provides charts and Venn diagrams of common DEGs for different drugs/concentrations.
  • FIG.14A is a chart and Venn diagram of common DEGs between 10 ⁇ M CA-4948 and 1 ⁇ M Compound 8.
  • FIG.14B is a chart and Venn diagram of common DEGs between 10 ⁇ M CA-4948 and 5 ⁇ M Compound 8.
  • FIG.14C is a chart and Venn diagram of common DEGs between 1 ⁇ M Compound 8 and 5 ⁇ M Compound 8.
  • FIGS.15A-15B provide canonical NF- ⁇ B target genes.
  • FIG.15A is a chart of canonical Nf ⁇ B target genes for different concentrations of Compound 8 and CA-4948.
  • FIG.15B is a plot of control versus 5 ⁇ M Compound 8 canonical NF- ⁇ B target genes.
  • FIGS.16A-16B provide signature genes on Compound 8 (by fold change).
  • FIG.16A is a chart of signature genes for different concentrations of Compound 8 and CA-4948.
  • FIG.16B is a plot of control versus 5 ⁇ M Compound 8.
  • FIG.17 depicts the short IRAK1/4 gene signature for Compound 8 (by Z-score).
  • FIG.18 is a chart of FLT3 wildtype THP-1 (left) and MDSL (right) cultured cells treated with DMSO and different concentrations of CA-4948 or Compound 8.
  • FIGS.19A-19F demonstrate that Compound 8 impairs leukemic colony formation in FLT3 wild type primary patient cells.
  • FIG.19A depicts colony formation data in FLT3 wild type AML(33766) patient cells.
  • FIG.19B depicts colony formation data in FLT3 wild type MDS(3328) patient cells.
  • FIG.19C depicts colony formation data in FLT3 wild type AML(2702) patient cells.
  • FIG.19D depicts colony formation data in FLT3 wild type DB1/ 147901903.2 46 AML(3438) patient cells.
  • FIG.19E depicts colony formation data in FLT3 wild type AML(2456) patient cells.
  • FIG.19F depicts colony formation data in FLT3 wild type AML(2239) patient cells.
  • FIG.20 is a chart of FLT3 mutant MOLM14 (D835Y) cultured cells treated with DMSO and different concentrations of gilteritinib, CA-4948 or Compound 8.
  • FIGS.21A-21B demonstrate that Compound 8 impairs leukemic colony formation in FLT3 mutant primary patient cells.
  • FIG.21A depicts colony formation data in FLT3 mutant AML(3930) patient cells.
  • FIG.21B depicts colony formation data in FLT3 mutant AML(2228) patient cells.
  • FIGS.22A-22B depict the creation of an IRAK1/4 signature (FIG.22A) and the analysis of the IRAK1/4 signature in patients (FIG.22B).
  • FIGS.23A-23I depict the analysis of primary AML blast colony forming assays of FLT3 wildtype patients.
  • FIGS.24A-24G depict the analysis of primary AML blast colony forming assays of FLT3 mutant patients.
  • FIGS.25A-25D demonstrate that Compound 8 potently inhibits leukemic stem cell progenitor function regardless of mutational status.
  • FIG.25A is a comparison between % inhibition of colony formation at 200 nM of Compound 8 across primary patient samples that are either wildtype or mutant for FLT3.
  • FIG.25B is a CFU comparison (WT vs mutant) and provides an estimation plot showing no significant difference between the two populations.
  • FIG.25C provides the statistical analysis for the data shown in FIG.25A and FIG.25B.
  • FIG. 25D is a chart of the mutational status of the corresponding FLT3 WT patient AML primary bone marrow blasts. *Similar mutational profiles were seen in FLT3 mutant AML patient samples (data not shown).
  • FIG.26 provides a graph and a table demonstrating that the survival of an AML animal model is increased when the animal is treated with Compound 8 or venetoclax compared to a control animal.
  • FIG.27 provides a graph demonstrating that Compound 8 prolongs survival in mice xenografted with MOLM14 FLT3-ITD (D835Y) compared to gilteritinib and CA-4948. DB1/ 147901903.2 47
  • Adaptive immune signaling stim is CD3-CD28 Dynabeads at 1:1 ratio (beads:cell).
  • Crisaborole is a control inhibitor that inhibits most inflammatory cytokines. The supernatants were collected and analyzed for GM-CSF, IFN ⁇ , IL- 1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70 (no changes), IL-13, IL-17A, IL-23, and TNF ⁇ .
  • WO 2018038988 Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed August 16, 2017;
  • U.S. Patent No.11,254,667 Substituted imidazo[1,2-a]pyridines as IRAK 1/4 and FLT3 inhibitors, issued February 2, 2022;
  • U.S. Publication No.2022/0213094 Substituted Imidazo[l,2-a]-pyridines as IRAK 1/4 and FLT3 Inhibitors, filed January 4, 2022;
  • U.S. Publication No.2020/0199123 Substituted imidazo[1,2-a]pyridines as IRAK 1/4 and FLT3 inhibitors, filed February 28, 2020;
  • Some embodiments of the disclosure include disclosed compounds. Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the disclosed compound. Still other embodiments of the disclosure include compositions for treating, for example, certain diseases using the disclosed compounds. Some embodiments include methods of using the disclosed compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating. Further embodiments include methods for making the disclosed compound. Yet further embodiments include methods for determining whether a particular patient is likely to be responsive to such treatment with the disclosed compounds and compositions. Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art. The abbreviations used herein have their conventional meaning within the chemical and biological arts.
  • alkyl means a monovalent, straight or branched hydrocarbon chain, which can be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C 1 -C 10 means one to ten carbons).
  • C 1 -C 7 alkyl or C 1 -C 4 alkyl refer to straight- or branched-chain saturated hydrocarbon groups having from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7), or 1 to 4 (e.g., 1, 2, 3, or 4), carbon atoms, respectively.
  • C 1 -C 7 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n- pentyl, s-pentyl, n-hexyl, and n-septyl.
  • Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl.
  • alkenyl means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) double bonds. Double bonds can occur in any stable point along the chain and the carbon-carbon double bonds can have either the cis or trans configuration.
  • this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, l-pentenyl-3-cyclohexenyl, and the like.
  • heteroalkenyl refers to heteroalkyl having one or more double bonds.
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2- propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.
  • alkynyl means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) triple bonds and that also may optionally include one or more (e.g.1, 2, 3, or 4) double bonds in the chain.
  • alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.
  • alkoxy means any of the above alkyl, alkenyl, or alkynyl groups which is attached to the remainder of the molecule by an DB1/ 147901903.2 50 oxygen atom (alkyl-O-).
  • alkoxy groups include, but are not limited to, methoxy (sometimes shown as MeO-), ethoxy, isopropoxy, propoxy, and butyloxy.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, or alkynyl group, as exemplified, but not limited by, -CH2CH2CH2CH2-.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the compounds disclosed herein.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • the term “cycloalkyl” means a monovalent, monocyclic or bicyclic, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered hydrocarbon group. The rings can be saturated or partially unsaturated.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicycloalkyls (e.g., bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds).
  • the ring is not aromatic.
  • heteroalkyl means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized, and the nitrogen heteroatom can optionally be quaternized.
  • the heteroatom(s) O, N, P, S, and Si can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • heteroalkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-.
  • DB1/ 147901903.2 51 heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO 2 R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like.
  • halogen or “halo” means monovalent Cl, F, Br, or I. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C1-C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like.
  • aryl means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 member aromatic hydrocarbon group and also means polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
  • aryl that is bicyclic one or both rings can be substituted.
  • heteroaryl means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon group, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen, oxygen, or sulfur atom, and the monocyclic or bicyclic ring system is aromatic.
  • Heteroaryl groups can contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple DB1/ 147901903.2 52 rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, 1H-pyrazol-4-yl, 1-Me-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 3,5-dimethylisoxazolyl, 1H- pyrrol-3-yl, 3,5-di-Me-pyrazolyl, and 1H-pyrazol-4-yl.
  • arylene and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively.
  • aryl can represent an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e. g.3-indolyl, 4-imidazolyl).
  • the aryl substituents are independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, C1-16alkyl, arylC1-16alkyl, C0-16alkyloxyC0-16alkyl, arylC 0-16 alkyloxyC 0-16 alkyl, C 0-16 alkylthioC 0-16 alkyl, arylC 0-16 alkylthioC 0-16 alkyl, C 0 - 1 6 alkylaminoC 0-16 alkyl, arylC 0-16 alkylaminoC 0-16 alkyl, di(arylC 1-16 alkyl)aminoC 0-16 alkyl, C 1 - 16alkylcarbonylC0-16alkyl, arylC1-16alkylcarbonylC0-16alkyl, C1-16alkylcarboxyC0-16alkyl, arylC1- 16alkylcarboxyC0-16alkyl,
  • Aryl includes but is not limited to pyrazolyl and triazolyl. DB1/ 147901903.2 53
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl “aralkyl” and the like are meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like), or a sulfur atom.
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like
  • sulfur atom e.g.
  • cycloalkyl (4- hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represents an aryl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • cycloalkyl and heterocycloalkyl also referred to as “heterocyclyl”, by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl or “heterocyclyl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen atom, oxygen atom, or sulfur atom, and the monocyclic or bicyclic ring system is not aromatic.
  • heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • heterocycloalkyl include, but are not limited to, 1-(1,2,5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, tetrahydropyran, pyrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, or pyrrolidin-4-yl), piperazinyl (e.g., piperazin-1-yl, piperazin-2-y
  • a bicyclic heterocyclyl if one ring is aromatic (e.g., monocyclic aryl or heteroaryl), then the other ring is not aromatic.
  • one or both rings can have one or more hetero atoms.
  • one or both rings can be substituted and the like.
  • a “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another DB1/ 147901903.2 54 substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.
  • hetero atom means an atom selected from nitrogen atom, oxygen atom, or sulfur atom.
  • hydroxy or “hydroxyl” means a monovalent -OH group.
  • acyl means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • oxo means an oxygen that is double bonded to a carbon atom.
  • alkylsulfonyl means a moiety having the formula -S(O2)-R', where R' is an alkyl group as defined above. R' can have a specified number of carbons (e.g., “C 1 -C 4 alkylsulfonyl”).
  • carbonyloxy represents a carbonyl group attached through an oxygen bridge.
  • linker refers to attachment groups interposed between substituents.
  • the linker includes amido (-CONH-R n or -NHCO-R n ), thioamido (-CSNH-R n or -NHCS-R n ), carboxyl (-CO 2 -R n or -OCOR n ), carbonyl (-CO-R n ), urea (-NHCONH-R n ), thiourea (-NHCSNH-R n ), sulfonamido (-NHSO2-R n or -SO2NH-R n ), ether (-O-R n ), sulfonyl (-SO 2 -R n ), sulfoxyl (-SO-R n ), carbamoyl (-NHCO 2 -R n or -OCONH-R n ), or amino (-NHR n ) linking moieties.
  • substituted e.g., as in substituted alkyl
  • substituted alkyl means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be replaced by one or more non-hydrogen substituents selected from the specified options. The replacement can occur at one or more positions.
  • DB1/ 147901903.2 55 means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be, but is not required to be substituted.
  • a “substituent group,” as used herein, means a non-hydrogen substituent group that may be, and preferably is, a group selected from the following moieties: (A) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO 2 H), nitro (-NO 2 ), -N(CH 3 ) 2 , ethynyl (-CCH), propynyl, sulfo (-SO 3 H), CONH 2 , - CON(CH 3 ) 2 , unsubstituted C 1 -C 7 alkyl, unsubstituted C 1 -C 7 heteroalkyl, unsubstit
  • a “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group, e.g., selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 4 -C 8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4-8-membered heterocycloalkyl.
  • a “lower substituent” or “lower substituent group,” as used herein, means a group, e.g., selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C5-C7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5-7-membered heterocycloalkyl.
  • Some compounds of the disclosure can have one or more chiral centers and can exist in and be isolated in optically active and racemic forms, for any of the one or more chiral centers. Some compounds can exhibit polymorphism.
  • the compounds of the present disclosure (e.g., Formula I) encompass any optically active, racemate, stereoisomer form, polymorphism, or mixtures thereof. If a chiral center does not provide an indication of its configuration (i.e., R or S) in a chemical structure, it should be considered to represent R, S or a racemate.
  • sample encompasses a sample obtained from a subject or patient.
  • the sample can be of any biological tissue or fluid.
  • samples include, but are not limited to, sputum, saliva, buccal sample, oral sample, blood, serum, mucus, plasma, urine, blood cells (e.g., white cells), circulating cells (e.g. stem cells or endothelial cells in the blood), tissue, core or fine needle biopsy samples, cell-containing body fluids, free floating nucleic acids, urine, stool, peritoneal fluid, and pleural fluid, tear fluid, or cells therefrom.
  • Samples can also include sections of tissues such as frozen or fixed sections taken for histological purposes or DB1/ 147901903.2 57 microdissected cells or extracellular parts thereof.
  • a sample to be analyzed can be tissue material from a tissue biopsy obtained by aspiration or punch, excision or by any other surgical method leading to biopsy or resected cellular material.
  • Such a sample can comprise cells obtained from a subject or patient.
  • the sample is a body fluid that include, for example, blood fluids, serum, mucus, plasma, lymph, ascitic fluids, gynecological fluids, or urine but not limited to these fluids.
  • the sample can be a non-invasive sample, such as, for example, a saline swish, a buccal scrape, a buccal swab, and the like.
  • blood can include, for example, plasma, serum, whole blood, blood lysates, and the like.
  • assessing includes any form of measurement, and includes determining if an element is present or not. The terms “determining,” “measuring,” “evaluating,” “assessing,” “analyzing,” and “assaying” can be used interchangeably and can include quantitative and/or qualitative determinations.
  • monitoring refers to a method or process of determining the severity or degree of the type of cancer or stratifying the type of cancer based on risk and/or probability of mortality. In some embodiments, monitoring relates to a method or process of determining the therapeutic efficacy of a treatment being administered to a patient.
  • outcome can refer to an outcome studied. In some embodiments, “outcome” can refer to survival / mortality over a given time horizon. For example, “outcome” can refer to survival / mortality over 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or longer.
  • an increased risk for a poor outcome indicates that a therapy has had a poor efficacy
  • a reduced risk for a poor outcome indicates that a therapy has had a good efficacy.
  • the term “high risk clinical trial” refers to one in which the test agent has “more than minimal risk” (as defined by the terminology used by institutional review boards, or IRBs).
  • a high risk clinical trial is a drug trial.
  • the term “low risk clinical trial” refers to one in which the test agent has “minimal risk” (as defined by the terminology used by IRBs).
  • a low risk clinical trial is one that is not a drug trial.
  • a low risk clinical trial is one DB1/ 147901903.2 58 that that involves the use of a monitor or clinical practice process.
  • a low risk clinical trial is an observational clinical trial.
  • the terms “modulated” or “modulation,” or “regulated” or “regulation” and “differentially regulated” can refer to both up regulation (i.e., activation or stimulation, e.g., by agonizing or potentiating) and down regulation (i.e., inhibition or suppression, e.g., by antagonizing, decreasing or inhibiting), unless otherwise specified or clear from the context of a specific usage.
  • the term “subject” refers to any suitable (e.g., treatable) member of the animal kingdom.
  • the subject is preferably a mammal.
  • the subject is preferably a human patient.
  • the subject may be a mammalian pediatric patient.
  • the pediatric patient is a mammalian (e.g., preferably human) patient under 18 years of age, while an adult patient is 18 or older.
  • the term “treating” (and its variations, such as “treatment” “treating,” “treat,” and the like) is, unless stated otherwise, to be considered in its broadest context and refers to obtaining a desired pharmacologic and/or physiologic effect.
  • treating may not necessarily imply or require that an animal is treated until total recovery. Accordingly, “treating” includes amelioration of the symptoms, relief from the symptoms or effects associated with a condition, decrease in severity of a condition, or preventing, preventively ameliorating symptoms, or otherwise reducing the risk of developing a particular condition. In some aspects, “treating” may not require or include prevention.
  • reference to “treating” an animal includes but is not limited to prophylactic treatment and therapeutic treatment. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or can be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease.
  • Treatment covers any treatment of a disease in a subject, preferably in a mammal (e.g., in a human), and may include one or more of: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression or elimination of the disease and/or relieving one or more disease symptoms.
  • treatment may be or DB1/ 147901903.2 59 include reducing such expression or signaling.
  • Treatment can also encompass delivery of an agent or administration of a therapy in order to provide for a pharmacologic effect, even in the absence of a disease or condition. Any of the compositions (e.g., pharmaceutical compositions) described herein can be used to treat a suitable subject.
  • “Therapeutically effective amount” means an amount effective to achieve a desired and/or beneficial effect. An effective amount can be administered in one or more administrations.
  • a therapeutically effective amount is an amount appropriate to treat an indication.
  • treating an indication is meant achieving any desirable effect, such as one or more of palliate, ameliorate, stabilize, reverse, slow, or delay disease progression, increase the quality of life, or to prolong life.
  • Such achievement can be measured by any suitable method, such as measurement of tumor size or blood cell count, or any other suitable measurement.
  • the term “marker” or “biomarker” refers to a biological molecule, such as, for example, a nucleic acid, peptide, protein, hormone, and the like, whose presence or concentration can be detected and correlated with a known condition, such as a disease state.
  • an mRNA “isoform” is an alternative transcript for a specific mRNA or gene. This term includes pre-mRNA, immature mRNA, mature mRNA, cleaved or otherwise truncated, shortened, or aberrant mRNA, modified mRNA (e.g. containing any residue modifications, capping variants, polyadenylation variants, etc.), and the like.
  • Antibody or “antibody peptide(s)” refer to an intact antibody, or a binding fragment thereof that competes with the intact antibody for specific binding; this definition also encompasses monoclonal and polyclonal antibodies. Binding fragments are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab′, F(ab′)2, Fv, and single-chain antibodies. An antibody other than a “bispecific” or “bifunctional” antibody is understood to have each of its binding sites identical.
  • An antibody substantially inhibits adhesion of a receptor to a counterreceptor when an excess of antibody reduces the quantity of receptor bound to DB1/ 147901903.2 60 counterreceptor by at least about 20%, 40%, 60% or 80%, and more usually greater than about 85% (as measured in an in vitro competitive binding assay).
  • Embodiments of the disclosure set forth herein include disclosed compounds (e.g., Compound 8).
  • Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the disclosed compound.
  • Still other embodiments of the disclosure include compositions (e.g., pharmaceutical compositions) for treating, for example, certain diseases using the disclosed compounds.
  • Some embodiments include methods of using the disclosed compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating (e.g., diseases such as cancer or blood disorders). Some embodiments include methods of determining whether a patient is suitable for, or likely to respond favorably to, a particular treatment. Further embodiments include methods for making the disclosed compounds. Additional embodiments of the disclosure are also discussed herein.
  • the present disclosure relates to or a salt, ester, solvate, optical isomer, geometric isomer, or embodiment, the compounds disclosed herein (i.e., Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof) are an IRAK1, IRAK4, IRAK1/4, and/or FLT3 inhibitor. In one embodiment, the compounds disclosed herein are IRAK1/4, panFLT3 inhibitors.
  • Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of less than about 55 nM, less than about 50 nM, less than about 45 nM, less than about 40 nM, less than about 35 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of between about 27 nM and about 17 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, DB1/ 147901903.2 61 geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of about 30 nM, about 29 nM, about 28 nM, about 27 nM, about 25 nM, about 24 nM, about 23 nM, about 22 nM, about 21 nM, about 20 nM, about 19 nM, about 18 nM, about 17 nM, about 16 nM, or about 15 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of between about 5 nM and about 0.05 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC 50 of about 5 nM, about 4.5 nM, about 4 nM, about 3.5 nM, about 3 nM, about 2.5 nM, about 2 nM, about 1.5 nM, about 1 nM, or about 0.5 nM.
  • the compound has IRAK4:IRAK1 potency ratio of less than about 70, less than about 60, less than about 50, less than about 40, less than about 30, or less than about 20.
  • the IRAK4:IRAK1 potency ratio is calculated from the IRAK1 and IRAK4 IC50 measurements.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC 50 of less than about 10 nM, less than about 8 nM, less than about 6 nM, less than about 4 nM, less than about 2 nM, or less than about 1 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC 50 of between about 2 nM and about 0.01 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC50 of about 2.5 nM, about 2.25 nM, about 2 nM, about 1.75 nM, about 1.5 nM, about 1.25 nM, about 1 nM, about 0.75 nM, about 0.5 nM, about 0.25 nM, about 0.1 nM, or about 0.075 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits NF-kB-mediated signaling.
  • inhibition of IRAK1 and IRAK4 inhibits NF-kB-mediated signaling.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits TLR signaling and IL-1 signaling.
  • the inhibition of IRAK1 and IRAK4 inhibits TLR signaling and IL-1 signaling.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits IRAK1, IRAK4, and FLT3 DB1/ 147901903.2 62
  • Methods the present disclosure provides a method of treating an inflammatory disease/disorder, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS) in a subject in need thereof, the method comprising administering to the subject Compound 8: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • the inflammatory disease/disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis.
  • the subject has or is suspected of having AML.
  • the AML is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML.
  • the AML is FLT3 wild type AML.
  • the AML is FLT3 mutant AML.
  • the subject has or is suspected of having MDS.
  • the MDS is MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2.
  • the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1, SRSF2, SF3B1, or ZRSR2.
  • the subject has FLT3 wild type AML.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, JAK2, ASXL1, ABL1, BCORL1, FBXW7, KDM6A, KRAS, SRSF2, TP53, CALR, ATRX, IDH1, IDH2, PDGFRA, SF3B1, GATA1, PTPN11, HRAS, MPL, PHF6, ATM, BCL11A, MLL3, TYK1, DB1/ 147901903.2 63 UTAF1, CTCF, CEBPA, ETV6, NOTCH1, STAG2, SET
  • the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, KIT, or BCOR. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of TET2, KIT, and BCOR. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, BRAF, CDKN2A, or UTX. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of TET2, BRAF, CDKN2A, and UTX.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of ZRSR2, TET2, NPM1, PTEN, DNMT3A, or EZH2. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of ZRSR2, TET2, NPM1, PTEN, DNMT3A, and EZH2. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, RUNX1, JAK2, DNMT3A, or ASXL1. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of TET2, RUNX1, JAK2, DNMT3A, and ASXL1.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of ABL1, ASXL1, BCORL1, CBL, CDKN2A, FBXW7, KDM6A, KIT, KRAS, PTEN, SRSF2, TET2, or TP53.
  • the subject has FLT3 wild type AML with a gene mutation in each of ABL1, ASXL1, BCORL1, CBL, CDKN2A, FBXW7, KDM6A, KIT, KRAS, PTEN, SRSF2, TET2, and TP53.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of ABL1, ASXL1, ATRX, BCOR, BCORL1, CALR, CDKN2A, DNMT3A, IDH1, KIT, KRAS, PDGFRA, PTEN, SF3B1, TET2, or TP53.
  • the subject has FLT3 wild type AML with a gene mutation in each of ABL1, ASXL1, ATRX, BCOR, BCORL1, CALR, CDKN2A, DNMT3A, IDH1, KIT, KRAS, PDGFRA, PTEN, SF3B1, TET2, and TP53.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of ASXL1, BCORL1, BRAF, CDKN2A, DNMT3A, EZH2, HRAS, KIT, KRAS, MPL, PHF6, PTEN, RUNX1, TET2, TP53, or WT1.
  • the subject has FLT3 wild type AML with a gene mutation in each of ASXL1, BCORL1, BRAF, CDKN2A, DNMT3A, EZH2, HRAS, KIT, KRAS, MPL, PHF6, PTEN, RUNX1, TET2, TP53, and WT1.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of ABL1, ASXL1, ATRX, BCORL1, CBL, CDKN2A, DNMT3A, GATA1, JAK2, KDM6A, KIT, KRAS, PTEN, PTPN11, SRSF2, TET2, or TP53.
  • the subject has FLT3 wild type AML with a gene mutation in each of ABL1, ASXL1, ATRX, BCORL1, CBL, CDKN2A, DNMT3A, GATA1, JAK2, KDM6A, KIT, KRAS, DB1/ 147901903.2 64 PTEN, PTPN11, SRSF2, TET2, and TP53.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of BCL11A, RUNX1, ATM, DNMT3A, CTCF, KIT, U2AF1, IDH1, TYK2, or MLL3. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of BCL11A, RUNX1, ATM, DNMT3A, CTCF, KIT, U2AF1, IDH1, TYK2, and MLL3.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of ABL1, ASXL1, BCORL1, BRAF, CDKN2A, CEBPA, DNMT3A, ETV6, EZH2, IDH2, KDM6A, KIT, KRAS, PTEN, RUNX1, SF3B1, TET2, TP53, or ZRSR2.
  • the subject has FLT3 wild type AML with a gene mutation in each of ABL1, ASXL1, BCORL1, BRAF, CDKN2A, CEBPA, DNMT3A, ETV6, EZH2, IDH2, KDM6A, KIT, KRAS, PTEN, RUNX1, SF3B1, TET2, TP53, and ZRSR2.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of ASXL1, ATRX, BCORL1, BRAF, DNMT3A, EZH2, FBXW7, GATA1, KDM6A, KIT, KRAS, NOTCH1, PTEN, RUNX1, STAG2, TET2, or TP53.
  • the subject has FLT3 wild type AML with a gene mutation in each of ASXL1, ATRX, BCORL1, BRAF, DNMT3A, EZH2, FBXW7, GATA1, KDM6A, KIT, KRAS, NOTCH1, PTEN, RUNX1, STAG2, TET2, and TP53.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of ABL1, ASXL1, BCORL1, CDKN2A, CEBPA, HRAS, IDH1, KDM6A, KRAS, NOTCH1, PTEN, SRSF2, or TP53.
  • the subject has FLT3 wild type AML with a gene mutation in each of ABL1, ASXL1, BCORL1, CDKN2A, CEBPA, HRAS, IDH1, KDM6A, KRAS, NOTCH1, PTEN, SRSF2, and TP53.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of ATRX, BCOR, BCORL1, BRAF, CDKN2A, FBXW7, KIT, NRAS, PTEN, RUNX1, STAG2, TET2, or TP53.
  • the subject has FLT3 wild type AML with a gene mutation in each of ATRX, BCOR, BCORL1, BRAF, CDKN2A, FBXW7, KIT, NRAS, PTEN, RUNX1, STAG2, TET2, and TP53.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of ABL1, ASXL1, BCOR, BCORL1, BRAF, CDKN2A, ETV6, FBXW7, KDM6A, KRAS, PTEN, PTPN11, RUNX1, SETBP1, SRSF2, TET2, TP53, or WT1.
  • the subject has FLT3 wild type AML with a gene mutation in each of ABL1, ASXL1, BCOR, BCORL1, BRAF, CDKN2A, ETV6, FBXW7, KDM6A, KRAS, PTEN, PTPN11, RUNX1, SETBP1, SRSF2, TET2, TP53, and WT1.
  • Compound 8, or a salt, ester, solvate, optical DB1/ 147901903.2 65 isomer, geometric isomer, or salt of an isomer thereof treats FLT3 wild type AML regardless of the additional AML mutational status of the subject.
  • the subject has FLT3 mutant AML with a FLT3-ITD mutation and a gene mutation in one or more of TET2, DNMT3A, or NPM1. In one embodiment, the subject has FLT3 mutant AML with a FLT3-ITD mutation and a gene mutation in each of TET2, DNMT3A, and NPM1. In one embodiment, the subject has FLT3 mutant AML with a FLT3- ITD mutation and/or a FLT3(D835Y) mutation. In one embodiment, the subject has FLT3 mutant AML with each of a FLT3-ITD mutation and a FLT3(D835Y) mutation.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ABL1, ATRX, BCORL1, BRAF, CDKN2A, DNMT3A, KDM6A, KRAS, PTEN, PTPN11, RUNX1, TET2, or TP53.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ABL1, ATRX, BCORL1, BRAF, CDKN2A, DNMT3A, KDM6A, KRAS, PTEN, PTPN11, RUNX1, TET2, and TP53.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ASXL1, BCORL1, CDKN2A, CEBPA, DNMT3A, FBXW7, HRAS, IDH1, JAK2, KIT, NPM1, NRAS, PDGFRA, PTEN, PTPN11, SF3B1, TET2, or TP53.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ASXL1, BCORL1, CDKN2A, CEBPA, DNMT3A, FBXW7, HRAS, IDH1, JAK2, KIT, NPM1, NRAS, PDGFRA, PTEN, PTPN11, SF3B1, TET2, and TP53.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ASXL1, BCORL1, BRAF, CBL, DNMT3A, ETV6, JAK2, KIT, PDGFRA, PHF6, PTEN, PTPN11, RUNX1, TET2, or TP53.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ASXL1, BCORL1, BRAF, CBL, DNMT3A, ETV6, JAK2, KIT, PDGFRA, PHF6, PTEN, PTPN11, RUNX1, TET2, and TP53.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ABL1, ASXL1, ATRX, BCORL1, CDKN2A, CEBPA, FBXW7, GATA1, KRAS, NOTCH1, PTEN, TET2, TP53, or WT1.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ABL1, ASXL1, ATRX, BCORL1, CDKN2A, CEBPA, FBXW7, GATA1, KRAS, NOTCH1, PTEN, TET2, TP53, and WT1.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ABL1, ASXL1, ATRX, BCORL1, CDKN2A,DNMT3A, ETV6, KDM6A, KIT, KRAS, NOTCH1, NRAS, PDGFRA, PTEN, PTPN11, RUNX1, SETBP1, TET2, DB1/ 147901903.2 66 or TP53.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ABL1, ASXL1, ATRX, BCORL1, CDKN2A,DNMT3A, ETV6, KDM6A, KIT, KRAS, NOTCH1, NRAS, PDGFRA, PTEN, PTPN11, RUNX1, SETBP1, TET2, and TP53.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ABL1, ASXL1, ATRX, BCORL1, BRAF, CBL, CDKN2A, ETV6, GNAS, HRAS, JAK2, KDM6A, PTEN, TET2, or TP53.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ABL1, ASXL1, ATRX, BCORL1, BRAF, CBL, CDKN2A, ETV6, GNAS, HRAS, JAK2, KDM6A, PTEN, TET2, and TP53.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ABL1, ASXL1, BCORL1, BRAF, CBL, CDKN2A, FBX, HRAS, IDH2, KDM6A, KIT, PTEN, RAD21, RUI, TET2, or TP53.
  • the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ABL1, ASXL1, BCORL1, BRAF, CBL, CDKN2A, FBX, HRAS, IDH2, KDM6A, KIT, PTEN, RAD21, RUI, TET2, and TP53.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats FLT3 mutant AML regardless of the additional AML mutational status of the subject.
  • the subject has MDS with a gene mutation in U2AF1.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats MDS regardless of the MDS mutational status of the subject.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of less than about 55 nM, less than about 50 nM, less than about 45 nM, less than about 40 nM, less than about 35 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of between about 27 nM and about 17 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of about 30 nM, about 29 nM, about 28 nM, about 27 nM, about 25 nM, about 24 nM, about 23 nM, about 22 nM, about 21 nM, about 20 nM, about 19 nM, about 18 nM, about 17 nM, about 16 nM, or about 15 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of less than about 30 nM, less than about 25 nM, less DB1/ 147901903.2 67 than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC 50 of between about 5 nM and about 0.05 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of about 5 nM, about 4.5 nM, about 4 nM, about 3.5 nM, about 3 nM, about 2.5 nM, about 2 nM, about 1.5 nM, about 1 nM, or about 0.5 nM.
  • the compound has IRAK4:IRAK1 potency ratio of less than about 70, less than about 60, less than about 50, less than about 40, less than about 30, or less than about 20.
  • the IRAK4:IRAK1 potency ratio is calculated from the IRAK1 and IRAK4 IC 50 measurements.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC50 of less than about 10 nM, less than about 8 nM, less than about 6 nM, less than about 4 nM, less than about 2 nM, or less than about 1 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC50 of between about 2 nM and about 0.01 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC 50 of about 2.5 nM, about 2.25 nM, about 2 nM, about 1.75 nM, about 1.5 nM, about 1.25 nM, about 1 nM, about 0.75 nM, about 0.5 nM, about 0.25 nM, about 0.1 nM, or about 0.075 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits NF-kB-mediated signaling.
  • inhibition of IRAK1 and IRAK4 inhibits NF-kB-mediated signaling.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits TLR signaling and IL-1 signaling.
  • the inhibition of IRAK1 and IRAK4 inhibits TLR signaling and IL-1 signaling.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits IRAK1, IRAK4, and FLT3.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits FLT3.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats AML and/or MDS in the subject by suppressing leukemic stem/progenitor cell (LSPC) function and inducing differentiation.
  • LSPC leukemic stem/progenitor cell
  • the inhibition of IRAK1 and DB1/ 147901903.2 68 IRAK4 by the compound of the disclosure promotes the suppression of LSPC function and the induction of differentiation in the subject with AML and/or MDS.
  • the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes and/or decreased expression of one or more IRAK1/4-associated genes. In one embodiment, the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes compared to a healthy control subject and/or decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject.
  • the subject in need thereof has elevated expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes.
  • the subject in need thereof has elevated expression of one or more IRAK1/4- associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B ⁇ AS1, and BAG3.
  • IRAK1/4- associated genes selected from
  • the subject in need thereof has elevated expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1,
  • the subject in need thereof has decreased expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes compared to a DB1/ 147901903.2 69 healthy control subject.
  • the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B ⁇ AS1, and BAG3.
  • IRAK1/4-associated genes selected from
  • the subject in need thereof has decreased expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1,
  • the subject in need thereof has increased secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines. In one embodiment, the subject in need thereof has increased secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN- ⁇ .
  • the subject in need thereof has increased secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines compared to a healthy control subject. In one embodiment, the subject in need thereof has increased secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN- ⁇ compared to the healthy control subject.
  • Compound 8 decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject and/or increases the expression of one of more DB1/ 147901903.2 70 IRAK1/4-associated genes found to be decreased in the subject.
  • Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8 and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8.
  • Compound 8 decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject.
  • Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes in the subject in need thereof.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50
  • IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DD
  • Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes in the subject in need thereof.
  • Compound 8 increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX,
  • IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438,
  • Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT
  • Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines in the subject in need thereof.
  • Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an DB1/ 147901903.2 72 isomer thereof decreases the secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN- ⁇ in the subject in need thereof.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in need thereof via parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in need thereof in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight.
  • composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered to the subject in need thereof.
  • the composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof further comprises one or more pharmaceutically acceptable carriers, excipients, or additives.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject.
  • the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject after the administration is stopped.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, DB1/ 147901903.2 73 about one week, about two weeks, about three weeks, or about a month after the administration is stopped.
  • the method further comprises administering Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, in combination with one or more additional agents selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody- drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an a chemotherapy agent
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in need thereof in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a gluococorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
  • the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof.
  • the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof.
  • the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor.
  • the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a DB1/ 147901903.2 74 pharmaceutically acceptable salt of any one thereof.
  • the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
  • one or more compositions comprising the one or more additional agents are administered to the subject in need thereof.
  • the one or more compositions comprising the one or more additional agents further comprise a pharmaceutically acceptable carrier, excipient, or additive.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered sequentially with the one or more additional agents.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered concurrently with the one or more additional agents.
  • the composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered sequentially with the composition comprising the one or more additional agents.
  • the composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered concurrently with the composition comprising the one or more additional agents.
  • the present disclosure provides a method of determining a subject with a disease/disorder that can be treated by the administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, the method comprising: determining that a subject with an inflammatory disease/disorder, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS) has elevated expression of one or more IRAK1/4- associated genes and/or decreased expression of one or more IRAK1/4-associated genes; and administering to the subject Compound 8: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, thus treating the inflammatory disease/disorder, AML, or MDS.
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes and/or decreased DB1/ 147901903.2 75 expression of one or more IRAK1/4-associated genes compared to a healthy control subject.
  • the inflammatory disease/disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis.
  • the subject has or is suspected of having AML.
  • the AML is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML.
  • the AML is FLT3 wild type AML.
  • the AML is FLT3 mutant AML.
  • the subject has or is suspected of having MDS.
  • the MDS is MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2.
  • the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1, SRSF2, SF3B1, or ZRSR2.
  • the subject has FLT3 wild type AML.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, JAK2, or ASXL1.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, KIT, or BCOR.
  • the subject has FLT3 wild type AML with a gene mutation in each of TET2, KIT, and BCOR.
  • the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, BRAF, CDKN2A, or UTX.
  • the subject has FLT3 wild type AML with a gene mutation in each of TET2, BRAF, CDKN2A, and UTX. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of ZRSR2, TET2, NPM1, PTEN, DNMT3A, or EZH2. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of ZRSR2, TET2, NPM1, PTEN, DNMT3A, and EZH2. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, RUNX1, JAK2, DNMT3A, or ASXL1.
  • the subject has FLT3 wild type AML with a gene mutation in each of TET2, RUNX1, JAK2, DNMT3A, and ASXL1.
  • Compound 8, or a salt, ester, DB1/ 147901903.2 76 solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats FLT3 wild type AML regardless of the additional AML mutational status of the subject.
  • the subject has FLT3 mutant AML with a FLT3-ITD mutation and a gene mutation in one or more of TET2, DNMT3A, or NPM1.
  • the subject has FLT3 mutant AML with a FLT3-ITD mutation and a gene mutation in each of TET2, DNMT3A, and NPM1.
  • the subject has FLT3 mutant AML with a FLT3- ITD mutation and/or a FLT3(D835Y) mutation.
  • the subject has FLT3 mutant AML with each of a FLT3-ITD mutation and a FLT3(D835Y) mutation.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats FLT3 mutant AML regardless of the additional AML mutational status of the subject.
  • the subject has MDS with a gene mutation in U2AF1.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats MDS regardless of the MDS mutational status of the subject.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC 50 of less than about 55 nM, less than about 50 nM, less than about 45 nM, less than about 40 nM, less than about 35 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC 50 of between about 27 nM and about 17 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC 50 of about 30 nM, about 29 nM, about 28 nM, about 27 nM, about 25 nM, about 24 nM, about 23 nM, about 22 nM, about 21 nM, about 20 nM, about 19 nM, about 18 nM, about 17 nM, about 16 nM, or about 15 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC 50 of less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC 50 of between about 5 nM and about 0.05 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of about 5 nM, about 4.5 nM, about 4 nM, about 3.5 nM, DB1/ 147901903.2 77 about 3 nM, about 2.5 nM, about 2 nM, about 1.5 nM, about 1 nM, or about 0.5 nM.
  • the compound has IRAK4:IRAK1 potency ratio of less than about 70, less than about 60, less than about 50, less than about 40, less than about 30, or less than about 20.
  • the IRAK4:IRAK1 potency ratio is calculated from the IRAK1 and IRAK4 IC50 measurements.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC 50 of less than about 10 nM, less than about 8 nM, less than about 6 nM, less than about 4 nM, less than about 2 nM, or less than about 1 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC 50 of between about 2 nM and about 0.01 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC50 of about 2.5 nM, about 2.25 nM, about 2 nM, about 1.75 nM, about 1.5 nM, about 1.25 nM, about 1 nM, about 0.75 nM, about 0.5 nM, about 0.25 nM, about 0.1 nM, or about 0.075 nM.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits NF-kB-mediated signaling.
  • inhibition of IRAK1 and IRAK4 inhibits NF-kB-mediated signaling.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits TLR signaling and IL-1 signaling.
  • the inhibition of IRAK1 and IRAK4 inhibits TLR signaling and IL-1 signaling.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits IRAK1, IRAK4, and FLT3.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits FLT3.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats AML and/or MDS in the subject by suppressing leukemic stem/progenitor cell (LSPC) function and inducing differentiation.
  • LSPC leukemic stem/progenitor cell
  • the inhibition of IRAK1 and IRAK4 by the compound of the disclosure promotes the suppression of LSPC function and the induction of differentiation in the subject with AML and/or MDS.
  • the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes and/or decreased expression of one or more IRAK1/4-associated genes.
  • the subject in need thereof has elevated expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, DB1/ 147901903.2 78 seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes.
  • the subject in need thereof has elevated expression of one or more IRAK1/4- associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B ⁇ AS1, and BAG3.
  • IRAK1/4- associated genes selected from
  • the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes compared to a healthy control subject and/or decreased expression of one or more IRAK1/4- associated genes compared to a healthy control subject.
  • the subject in need thereof has elevated expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes compared to a healthy control subject.
  • the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B ⁇ AS1, and BAG3 compared to the healthy control subject.
  • the subject in need thereof has elevated expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1,
  • the subject in need thereof has decreased expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes.
  • the subject in need thereof has decreased expression of one or more IRAK1/4- associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B ⁇ AS1, and BAG3.
  • IRAK1/4- associated genes selected from
  • the subject in need thereof has decreased expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1,
  • the subject in need thereof has decreased expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes compared to a healthy control subject.
  • the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, DB1/ 147901903.2 80 SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B ⁇ AS1, and BAG3
  • the subject in need thereof has decreased expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1,
  • the subject in need thereof has elevated secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines. In one embodiment, the subject in need thereof has elevated secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN- ⁇ .
  • the subject in need thereof has elevated secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines compared to a healthy control subject. In one embodiment, the subject in need thereof has elevated secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN- ⁇ compared to the healthy control subject.
  • Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8 and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8.
  • Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the DB1/ 147901903.2 81 expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes in the subject in need thereof.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50
  • IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DD
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX
  • Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT
  • Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines in the subject in need thereof.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in need thereof via parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in need thereof in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in a dosage of from about 1 ⁇ M to about 10,000 ⁇ M, about 1 ⁇ M to about 950 ⁇ M, about 1 ⁇ M to about 900 ⁇ M, about 1 ⁇ M to about 850 ⁇ M, about 1 ⁇ M to about 700 ⁇ M, about 1 ⁇ M to about 650 ⁇ M, about 1 ⁇ M to about 600 ⁇ M, about 1 ⁇ M to about 550 ⁇ M, DB1/ 147901903.2 84 about 1 ⁇ M to about 500 ⁇ M, about 1 ⁇ M to about 450 ⁇ M, about 1 ⁇ M to about 400 ⁇ M, about 1 ⁇ M to about 350 ⁇ M, about 1 ⁇ M to about 300 ⁇ M, about 1 ⁇ M to about 250 ⁇ M, about 1 ⁇ M to about 200 ⁇ M, about 1 ⁇ M to about 150 ⁇
  • composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered to the subject in need thereof.
  • the composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof further comprises one or more pharmaceutically acceptable carriers, excipients, or additives.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject.
  • the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats the inflammatory disease/disorder, AML, or MDS in the subject while the compound is administered to the subject.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject after the administration is stopped.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped.
  • the method further comprises administering Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, in combination with one or more additional agents selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue DB1/ 147901903.2 85 (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody- drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in need thereof in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a gluococorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
  • the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof.
  • the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof.
  • the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor.
  • the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof.
  • the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
  • one or more compositions comprising the one or more additional agents are administered to the subject in need thereof.
  • the one or more compositions comprising the one or more additional agents further comprise a pharmaceutically acceptable carrier, excipient, or additive.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered DB1/ 147901903.2 86 sequentially with the one or more additional agents.
  • Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered concurrently with the one or more additional agents.
  • the composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered sequentially with the composition comprising the one or more additional agents.
  • the composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered concurrently with the composition comprising the one or more additional agents.
  • a method of treating an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in a subject in need thereof comprising administering to the subject a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof.
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • Clause 14 The method of any one of clauses 12, 12a, or 13, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, DB1/ 147901903.2 91 SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO
  • Clause 17 The method of any one of clauses 1 to 16, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more IRAK1/4- associated genes in the subject and/or increases the expression of one of more IRAK1/4- associated genes in the subject. Clause 17a.
  • Clause 17d The method of any one of clauses 17, 17a, 17b, or 17c, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of the one or more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and/or increases the expression of the one or more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • Clause 17e The method of any one of clauses 17 to 17d, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA- 4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject.
  • Clause 17f The method of any one of clauses 17 to 17e, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric DB1/ 147901903.2 95 isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 18.
  • Clause 18a The method of any one of clauses 17 to 18, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KC
  • Clause 19 The method of any one of clauses 17 to 17f, 18, or 18a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DU
  • Clause 19a The method of any one of clauses 17 to 17e, 18, 18a, or 19, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, E
  • Clause 20 The method of any one of clauses 17 to 17f, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound DB1/ 147901903.2 100 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof increases the expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1,
  • Clause 20a The method of any one of clauses 17 to 17f or 20, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof increases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002,
  • Clause 21 The method of any one of clauses 17 to 17f, 20, or 20a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP
  • Clause 21a The method of any one of clauses 17 to 17f, 20, 20a, or 21 wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECH
  • Clause 22 The method of any one of clauses 1 to 21a, wherein the subject in need thereof has elevated expression of one or more NF ⁇ B-associated genes and/or decreased expression of one or more NF ⁇ B-associated genes.
  • Clause 22a The method of clause 22, wherein the subject in need thereof has elevated expression of one or more NF ⁇ B-associated genes compared to a healthy control subject, and/or decreased expression of one or more NF ⁇ B-associated genes compared to a healthy control subject.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Clause 24 The method of clause 22 or 22a, wherein the subject in need thereof has decreased expression of one or more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, DB1/ 147901903.2 107 HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL
  • Clause 25 The method of any one of clauses 1 to 24, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more NF ⁇ B-associated genes found to be elevated in the subject and/or increases the expression of one of more NF ⁇ B-associated genes found to be decreased in the subject.
  • Clause 25a The method of any one of clauses 1 to 24, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or
  • Clause 25c The method of any one of clauses 25, 25a, or 25b, wherein the administration of Compound 8 decreases the expression of the one or more NF ⁇ B-associated genes found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and/or increases the expression of the one or more NF ⁇ B-associated genes found to be decreased in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, DB1/ 147901903.2 110 GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11
  • Clause 26a The method of any one of clauses 25 to 26, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Clause 27 The method of any one of clauses 25 to 25f, 26, or 26a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one or more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Clause 27a The method of any one of clauses 25 to 25f, 26, 26a, or 27 wherein Compound 8, Compound 9, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one or more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL
  • Clause 27b The method of any one of clauses 1 to 27a, wherein the subject in need thereof has elevated secretion of one or more cytokines, optionally wherein the one or more cytokines are selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM- CSF, and IFN- ⁇ .
  • Clause 27e The method of any one of clauses 27a to 27e, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the secretion of one or more cytokines found to be elevated in the subject, optionally wherein the compound decreases the secretion of one or more cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN- ⁇ in the subject.
  • cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN- ⁇ in the subject.
  • Clause 27g The method of clause 27e or 27f, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of the one or more cytokines found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and/or increases the expression of the one or more cytokines found to be decreased in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • Clause 27h The method of clause 27e or 27f, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of the one or more cytokines found to be elevated in the subject before the administration of Compound 8, or
  • Clause 35a The method of any one of clauses 1 to 35, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody- drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist,
  • Clause 36 The method of clause 35 or 35a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
  • Clause 39a The method of any one of clauses 38, 38a, or 39, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof.
  • Clause 40a The method of any one of clauses 39, 39a, or 40, wherein the combination of Compound 8, or a salt, ester, DB1/ 147901903.2 122 solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 41.
  • the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof.
  • the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof.
  • a method of determining whether a subject with a an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic DB1/ 147901903.2 123 syndrome (MDS) can be treated by the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA- 4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, the method comprising: determining whether the subject has elevated expression of one or more IRAK1/4- associated genes and/or decreased expression of one or more IRAK1/4-associated genes, wherein the IRAK1/4-associated genes are selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC
  • IRAK1/4-associated genes are selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B ⁇ AS1, and BAG3.
  • Clause 48a The method of clause 47 or 48, wherein the method comprises determining whether a subject with an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be treated by the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • Clause 49 The method of any one of clauses 47, 48, or 48a, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes compared to a healthy control subject and/or decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject.
  • IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, G
  • IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42
  • DB1/ 147901903.2 128 Clause 52.
  • Clause 54 The method of any one of clauses 47 to 53, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one of more IRAK1/4- associated genes found to be elevated in the subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject.
  • Clause 54a The method of any one of clauses 47 to 53, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or
  • Clause 54c The method of any one of clauses 54 to 54b, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of the one or more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and/or increases the expression of the one or more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof.
  • Clause 54d The method of any one of clauses 54 to 54c, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more IRAK1/4- associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject.
  • Clause 54e The method of any one of clauses 54 to 54c, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (
  • Clause 55a The method of any one of clauses 54 to 54e or 55, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, DB1/ 147901903.2 134 CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM
  • Clause 56 The method of any one of clauses 54 to 54e, 55, or 55a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound DB1/ 147901903.2 136 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFM
  • Clause 56a The method of any one of clauses 54 to 54e, 55, 55a, or 56, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COM
  • Clause 57a The method of any one of clauses 54 to 54e or 57, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14
  • Clause 58 The method of any one of clauses 54 to 54e, 57, or 57a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, DB1/ 147901903.2 141 ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1,
  • Clause 58a The method of any one of clauses 54, 54a, 54b, 57, or 58, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K,
  • a method of determining whether a subject with an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be treated by the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, the method comprising: determining whether the subject has elevated expression of one or more NF ⁇ B-associated genes and/or decreased expression of one or more NF ⁇ B-associated genes, wherein the NF ⁇ B-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A,
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Clause 59a The method of clause 59, wherein the method comprising determining whether a subject with an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be treated by the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, DB1/ 147901903.2 144 IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10,
  • Clause 62 The method of any one of clauses 59, 59a, 60, or 61, wherein the subject in need thereof has decreased expression of one or more NF ⁇ B-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL
  • Clause 63 The method of any one of clauses 59 to 62, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one of more NF ⁇ B-associated genes found to be elevated in the subject and/or increases the expression of one of more NF ⁇ B-associated genes found to be decreased in the subject.
  • Clause 63a The method of any one of clauses 59 to 62, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib
  • Clause 63d The method of any one of clauses 63 to 63c, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one or more NF ⁇ B-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more NF ⁇ B-associated genes found to be decreased in the subject compared to a healthy control subject.
  • Clause 63e The method of any one of clauses 63 to 63d, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more NF ⁇ B-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more NF ⁇ B-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 64.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Clause 64a The method of any one of clauses 63 to 63e or 64, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more NF ⁇ B-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Clause 65 The method of any one of clauses 63 to 63e, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one or more NF ⁇ B-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • a method of determining whether a subject with an inflammatory disease or disorder, or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), can be treated by the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA- 4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, the method comprising: determining whether the subject has an elevated secretion of one or more cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM- CSF, and IFN- ⁇ .
  • cytokines selected from: TNF- ⁇ ,
  • Clause 65c The method of clause 65b, wherein the method comprises determining whether a subject with an inflammatory disease or disorder, or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), can be treated by the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • any one of clauses 47 to 66a wherein the inflammatory disease/disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, and colitis.
  • the inflammatory disease/disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, and colitis.
  • Clause 73a The method of any one of clauses 47 to 73, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC 50 of less than about 40 nM. Clause 74.
  • Clause 82 The method of clause 80 or 81, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped. Clause 82.
  • any one of clauses 47 to 81a wherein the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous DB1/ 147901903.2 158 administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous DB1/ 147901903.2 158 administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • Clause 83a The method of any one of clauses 47 to 83, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight or Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in a dosage of from about 0.35 mg to about 70,000 mg.
  • Clause 84 Clause 84.
  • Clause 84a The method of any one of clauses 47 to 84, wherein Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor
  • Clause 85 The method of clause 84 or 84a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound DB1/ 147901903.2 160 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
  • Clause 88a The method of any one of clauses 87, 87a, or 88, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof.
  • Clause 89 Clause 89.
  • Clause 89a The method of any one of clauses 88, 88a, or 89, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof.
  • Clause 90 Clause 90.
  • a method of treating an inflammatory disease ordisorder, or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in a subject in need thereof comprising administering to the subject Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof.
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • the inflammatory disease or disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis.
  • the inflammatory disease or disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis.
  • Clause 103
  • Clause 114 The method of any one of clauses 112, 112a, or 113, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B
  • Clause 117 The method of any one of clauses 101 to 116, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the DB1/ 147901903.2 170 expression of one of more IRAK1/4-associated genes found to be elevated in the subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject.
  • Clause 117a The method of any one of clauses 101 to 116, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948
  • Clause 117c The method of any one of clauses 117 to 117b, wherein the administration of Compound 8 decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof and/or wherein the administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject before the administration of or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof.
  • Clause 117e The method any one of clauses 117 to 117d, wherein the administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 117f.
  • Clause 118a The method of any one of clauses 117 to 117e or 118, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14,
  • Clause 119a The method of any one of clauses 117 to 117e, 118, 118a, or 119, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM
  • Clause 120a The method of any one of clauses 117 to 117e or 120, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC
  • Clause 121 The method of any one of clauses 117 to 117e, 120, or 120a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DD
  • Clause 122 The method of any one of clauses 101 to 121a, wherein the subject in need thereof has elevated expression of one or more NF ⁇ B-associated genes and/or decreased expression of one or more NF ⁇ B-associated genes.
  • Clause 122a The method of clause 122, wherein the subject in need thereof has elevated expression of one or more NF ⁇ B-associated genes compared to a healthy control subject and/or decreased expression of one or more NF ⁇ B-associated genes compared to a healthy control subject.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Clause 124 The method of clause 122 or 122a, wherein the subject in need thereof has decreased expression of one or more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL
  • Clause 125 The method of any one of clauses 101 to 124, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one of more NF ⁇ B-associated genes found to be elevated in the subject and/or increases the expression of one of more NF ⁇ B-associated genes found to be decreased in the subject.
  • Clause 125a The method of any one of clauses 101 to 124, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R
  • Clause 125c The method any one of clauses 125 to 125b, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one of more NF ⁇ B-associated genes found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof and/or increases the expression of one of more NF ⁇ B-associated genes found to be decreased in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • Clause 125g The method of any one of clauses 101 to 124, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one of more NF ⁇ B-associated genes in the subject and/or increases the expression of one of more NF ⁇ B-associated genes in the subject.
  • Clause 126 The method of any one of clauses 101 to 124, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Clause 126a The method of any one of clauses 125 to 125g or 126, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, DB1/ 147901903.2 188 GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL
  • Clause 127 The method of any one of clauses 125 to 125g, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof increases the expression of one or more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, DB1/ 147901903.2 189 ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Clause 127a The method of any one of clauses 125 to 125g or 127, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof increases the expression of one or more NF ⁇ B-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, DB1/ 147901903.2 191 IL
  • Clause 128 The method of any one of clauses 101 to 127a, wherein the subject in need thereof has elevated secretion of one or more cytokines.
  • Clause 128a The method of clause 128, wherein the subject in need thereof has elevated secretion of one or more cytokines compared to a healthy control subject.
  • Clause 129. The method of clause 128 or 128a, wherein the subject in need thereof has elevated secretion of one or more cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN- ⁇ .
  • Clause 130c The method of any one of clauses 130 to 130b, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the secretion of one of more cytokines found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 130d.
  • Clause 131a The method of any one of clauses 130 to 130e or 131, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the secretion of one or more cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN- ⁇ in the subject.
  • cytokines selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN- ⁇ in the subject.
  • any one of clauses 101 to 134 wherein the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • any one of clauses 101 to 141a further comprising administering to the subject one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an m
  • Clause 143 The method of any one of clauses 101 to 142, further comprising administering to the subject at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
  • Clause 144 The method of clause 142 or 143, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • Clause 146 The method of clause 145 or 145a, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases survival of the subject, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof.
  • Clause 146a The method of any one of clauses 145, 145a, or 146, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof.
  • Clause 147a The method of any one of clauses 146, 146a, or 147, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof.
  • glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof.
  • DB1/ 147901903.2 199 Clause 151.
  • the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor.
  • Clause 152. The method of clause 151, wherein the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof.
  • Clause 153 The method of clause 142 or 143, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
  • Clause 154a The method of clause 154, wherein the subject has elevated expression of one or more IRAK1/4-associated genes compared to a healthy control subject and/or a decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject. Clause 155.
  • IRAK1/4-associated genes are selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B ⁇ AS1, and BAG3.
  • Clause 156 The method of any one of clauses 154, 154a, or 155, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, DB1/ 147901903.2 202 MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279,
  • Clause 158 The method of clause 154 or 154a, wherein the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1,
  • Clause 160 The method of any one of clauses 154 to 159, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject.
  • Clause 160a The method of any one of clauses 154 to 159, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib),
  • Clause 160c The method of any one of clauses 160 or 160b, wherein the administration of Compound 8, or salt of an isomer of any decreases the expression of one of more IRAK1/4- associated genes found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • Clause 160d Clause 160d.
  • Clause 162 The method of any one of clauses 160 to 160e, 161, or 161a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT
  • Clause 162a The method of any one of clauses 160 to 160e, 161, 161a, or 162 wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K,
  • Clause 163a The method of any one of clauses 160 to 160e or 163, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof increases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, DB1/ 147901903.2 215 CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2,
  • Clause 164 The method of any one of clauses 160 to 160e, 163, or 163a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, DB1/ 147901903.2 217 geometric isomer, or salt of an isomer of any one thereof increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFM
  • Clause 164a The method of any one of clauses 160 to 160e, 163, 163a, or 164 wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COM
  • a method of determining whether a subject an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be treated by the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, the method comprising: determining whether the subject has elevated expression of one or more NF ⁇ B-associated genes and/or decreased expression of one or more NF ⁇ B-associated genes, wherein the NF ⁇ B-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, AD
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL
  • Clause 165a The method of clause 165, wherein the subject has elevated expression of one or more NF ⁇ B-associated genes compared to a healthy control subject and/or a decreased expression of one or more NF ⁇ B-associated genes compared to a healthy control subject.
  • the method of clause 165 or 165a, wherein the subject in need thereof has elevated expression of one or more NF ⁇ B-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Clause 167 The method of clause 165 or 165a, wherein the subject in need thereof has decreased expression of one or more NF ⁇ B-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL
  • Clause 168 The method of any one of clauses 165 to 167, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound DB1/ 147901903.2 222 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more NF ⁇ B-associated genes found to be elevated in the subject and/or increases the expression of one of more NF ⁇ B-associated genes found to be decreased in the subject.
  • Clause 168a The method of any one of clauses 165 to 167, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound DB1/ 147901903.2 222 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13,
  • Clause 168c The method of any one of clauses 168 to 168b, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more NF ⁇ B-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more NF ⁇ B-associated genes found to be decreased in the subject compared to a healthy control subject.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Clause 169a The method of any one of clauses 168 to 168d or 169, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more NF ⁇ B-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Clause 170 The method of any one of clauses 168 to 168d, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof increases the expression of one or more NF ⁇ B-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • Clause 170a The method of any one of clauses 168 to 168d or 170, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof increases the expression of one or more NF ⁇ B-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B.
  • FCER2/CD23 FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12
  • a method of determining whether a subject with an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic DB1/ 147901903.2 229 syndrome (MDS) can be treated by the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA- 4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, the method comprising: determining whether the subject has elevated secretion of one or more cytokines, wherein the one or more cytokines are selected from: TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23,
  • Clause 170c The method of clause 170b, wherein the subject has elevated expression of one or more cytokines compared to a healthy control subject and/or a decreased expression of one or more cytokines compared to a healthy control subject.
  • Clause 171. The method of any one of clauses 154 to 170c, further comprising administering to the subject Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof.
  • Clause 171a The method of any one of clauses 154 to 170c or 171, further comprising administering to the subject Compound 8: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 172.
  • any one of clauses 154 to 171a wherein the inflammatory disease or disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis.
  • Clause 178a The method of any one of clauses 154 to 178, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of less than about 40 nM. Clause 179.
  • Clause 192 The method of clause 190 or 191, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped. Clause 192.
  • any one of clauses 171 to 191a further comprising administering to the subject one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, DB1/ 147901903.2 235
  • Clause 192 The method of any one of clauses 171 to 191, further comprising administering to the subject at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
  • a BCL2 inhibitor a BTK inhibitor
  • a glucocorticoid a CDK inhibitor
  • a DNA methyltransferase inhibitor Clause 193.
  • Clause 193 wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • Clause 195a The method of any one of clauses 194, 194a, or 195, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof.
  • Clause 196 The method of any one of clauses 194, 194a, or 195, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof.
  • Clause 196a The method of any one of clauses 195, 195a, or 196, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof.
  • Clause 197 The method of any one of clauses 195, 195a, or 196, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof.
  • glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof.
  • the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor.
  • the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof.
  • NF-kB NF-kB reporter system expressed in human AML cells (THP1) was used to measure NF-kB dependent activation in response to a variety of IRAK4, IRAK1, or IRAK1/4 antagonists.
  • the cells are highly responsive to both TLR agonists as well as to IL-1 ⁇ , which allows for measurement of IRAK-mediated antagonism of multiple receptor-mediated pathways.
  • the IRAK1 selective covalent inhibitor JH-X-119-01 does not inhibit signaling against either the TLR or the IL-1 receptor agonist.
  • IRAK4 nor IRAK1 inhibition alone is sufficient to fully inhibit NF-kB- mediated signaling through multiple receptor mediated pathways.
  • the activity of a series of IRAK4/IRAK1 inhibitors was examined in AML cells. This allowed for a study of the effect of adding in additional inhibitory activity at IRAK1 on the background of high potency IRAK4 inhibitors.
  • IL-1 ⁇ 9.3 and 227 nM for Compound 15 and Compound 14, respectively).
  • Example 2 Introduction Leukemic cells exhibit dysregulation of innate immune signaling pathways upon diagnosis, and these pathways become further activated in drug resistance.
  • the Interleukin-1 receptor associated kinase 1 and 4 (IRAK1/IRAK4) kinase complex is part of a critical signaling node that becomes activated in these dysregulated pathways (reviewed in J Bennett and DT Starczynowski, Curr Opin Hematol 2022).
  • IRAK1 and IRAK4 utilize distinct and overlapping signaling pathways wherein IRAK1 compensates for IRAK4 inhibition in the setting of leukemia. Therefore, IRAK4 inhibition is insufficient for full efficacy in the setting of leukemia.
  • the IRAK4 inhibitors are currently under investigation for the treatment of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) and have shown encouraging, though modest responses in clinical studies. It has recently been demonstrated that limited responses to IRAK4 inhibitors in the leukemic setting can be explained by a compensated upregulation and activation of IRAK1, and the need to inhibit both IRAK1 and IRAK4 to achieve maximal therapeutic efficacy (JR Bennett et.
  • Hybrid LCMS (Immunoaffinity LC-MS/MS), also called Affinity-Capture LCMS was used to combine a selective enrichment step (typically an antibody enrichment on beads or columns) with the selectivity and sensitivity provided by LC-MS/MS (FIG.8B).
  • a selective enrichment step typically an antibody enrichment on beads or columns
  • FOG.8B selectivity and sensitivity provided by LC-MS/MS
  • Compound 8 was plated at concentrations between 0.2 ⁇ M and 5 ⁇ M in FLT3 wild type (WT) samples and at concentrations between 1 nM and 200 nM for FLT3 mutants.
  • CA-4948 was DB1/ 147901903.2 245 plated at concentrations between 1 ⁇ M and 50 ⁇ M. Then the mixture was vortexed and plated at least in duplicates. Plates were incubated in a tissue culture incubator at 37 °C and supplemented with 5% CO 2 for 10-16 days. Next, the colonies were imaged and analyzed.
  • Clonogenic progenitors of human AML-blast CFC were set up in a methylcellulose-based assay.
  • Human bone marrow mononuclear cells from forty-seven four distinct AML patients which were either FLT3 wild type or FLT3 mutant were stored in the gaseous phase of liquid nitrogen.
  • batches of 6-8 vials were thawed rapidly, the contents of each vial were diluted in 10 mL of Iscove’s modified Dulbecco’s medium containing 10% fetal bovine serum (IMDM + 10% FBS) and washed by centrifugation (approximately 1500 r.p.m.
  • AML marrow samples tested seventeen AML marrow samples, 8 derived from FLT3 mutants and 9 from FLT3 WT supported clonal growth. Based on whether the AML patients were characterized as FLT3 mutants or wild types, they were treated with various compounds. The test compounds were added to the methylcellulose and the tubes vortexed to ensure equal distribution of the test compounds throughout the matrix. Bone marrow cells from all 47 AML patients were added to the tubes of methylcellulose and vortexed. Triplicate cultures were initiated in 35 mm dishes and dispensed by positive displacement. The cultures were incubated for 14 days. AML-blast CFC were assessed microscopically and scored by trained personnel in situ.
  • test compounds Three test compounds (Compound 8, CA-4948, and Gilteritinib) were received as 10 mM stocks.
  • the FLT3 WT samples were treated with Compound 8 at 5, 1, and 0.2 ⁇ M.
  • the 10 mL stock was diluted 1:1 with DMSO to generate a 5 mM stock and then serial 1:5 dilutions were prepared again in DMSO to generate 1 and 0.2 mM working stocks that were 1000 X the required testing concentration.
  • the working stock concentrations were added 1:1000 v/v to the methylcellulose-based medium, the DB1/ 147901903.2 246 final desired concentrations were achieved.
  • 13.2 ⁇ L of the 10 mM stock was added.
  • DMSO was added as the solvent control for the mutant AML- blast CFC assay at 0.1% final volume.
  • NF- ⁇ B Reporter assay Performed according to THP-1-Blue NF- ⁇ B cells and QUANTI- Blue reagent manufacturing protocol (InvivoGen).
  • Colony forming units (CFU) Primary AML patient samples were obtained from Discovery life Sciences (DLS) and tested in a methylcellulose assay.
  • Biochemical and Cell-based Kinase inhibitory assays Kinase inhibitory data and cell- based kinase assays were obtained using the RBC HotSpot® Kinase and NANOBRET® Assay, respectively. The binding kinetics assay was performed using KINETICfinder® TR-FRET assay.
  • Xenograft Survival analysis was performed in NSG-SGM3 mice xenografted with MOLM14 FLT3-ITD (D835Y) cells.
  • RNASeq THP-1 cells were treated in liquid culture for 24 hr. Total RNA was extracted and RNAseq was performed at 30M reads per sample.
  • Statistical analysis All data were plotted using Graphpad Prism, and statistical significance was determined using T-test. Results and Discussion Compound 8 is a highly potent IRAK1/IRAK4/panFLT3 inhibitor that exhibits superior potency and therapeutic efficacy vs. IRAK4 inhibitor compounds in the FLT3 WT as well as the FLT3 mutant setting.
  • Compound 8 exhibited >100-fold selectivity vs.89% of the Kinome as measured in the Reaction Biology 374 kinase panel (FIG.9), with an IC 50 of 23, ⁇ 1.29, and ⁇ 0.5nM at IRAK1, IRAK4, and FLT3 respectively. Higher kinase selectivity was seen in cell-based assays vs. DB1/ 147901903.2 247 biochemical assays, where high potency kinase antagonist activity was also observed against PHKg1, PDGFR ⁇ , RET, CLK1, and CLK4 (Table 2). Table 2.
  • FIG.10 depicts the antagonism of the NF- ⁇ B response of PAM3CSK4 through the TLR2 receptor (top) and the antagonism of the NF- ⁇ B response of IL-1 ⁇ through the IL-1 receptor (bottom), wherein the error bars represent SEM from triplicate replicates. The experiment was replicated two additional times with similar results. Complete antagonism of signaling through both receptor pathways is only seen with the IRAK1/4 inhibitor (Compound 8).
  • PCA Principal Component Analysis
  • FIG.11A is a principal component analysis (PCA) plot showing the variation between samples. Reads were aligned with STAR DB1/ 147901903.2 248 (Spliced Transcripts Alignment to a Reference) and counted with featureCounts (package: subread) to obtain gene-level quantifications. Alignment rates were above 70% in all experiments.
  • FIGS.11B-11C are plots of showing the Z-score (blue downregulated, red upregulated) of the relative expression of NF- ⁇ B target genes (FIG.11B, genes listed in Table 4 of Appendix A) and IRAK1/4 dependency genes (FIG.11C, genes listed in Table 5 of Appendix A).
  • DEGs Differentially Expressed Genes
  • FIGS.13A-13C provide charts of DEGs for controls versus different concentrations of Compound 8 and CA-4948.
  • FIGS.14A-14C provide Venn diagrams showing overlapping DEGs (top) and charts of common DEGs (bottom) for 10 ⁇ M CA-4948 and 1 ⁇ M Compound 8 (FIG. 14A), 10 ⁇ M CA-4948 and 5 ⁇ M Compound 8 (FIG.14B), and 1 ⁇ M Compound 8 and 5 ⁇ M Compound 8 (FIG.14C).
  • FIGS.16A-16B depict signature genes on Compound 8 (FIG.16A) and their fold change (FIG 16B).
  • FIG.17 provides a short IRAK1/4 signature for Compound 8 (by Z-score), with the genes listed in Table 6 of Appendix A. Table 3.
  • AML Blast Colony Forming Unit (CFU) Data To obtain the AML blast CFU data, 50 primary AML PBMC samples were obtained, including 25 FLT3 mutant samples (23 samples received and plated; 7 grew colonies (meets expected 30-40% growth rate)) and 25 FLT3 WT samples (24 samples plated; 9 grew colonies DB1/ 147901903.2 249 (meets expected 30-40% growth rate)).
  • Compound 8 inhibited leukemia stem cell progenitor function as measured by the colony formation assay in methylcellulose with higher potency than IRAK4 inhibitor compounds that lack IRAK1 activity such as CA-4948 (Emavusertib) (FIGS.19A-19F: FLT3 wildtype patients, FIGS.21A-21B: FLT3 mutant patients). This activity was independent of patient mutational status.
  • IRAK4 Long isoform of IRAK4 (FIGS.19A-19F and FIGS.21A-21B), implying that the IRAK1/4/panFLT3 inhibitor Compound 8 will have activity across a broader patient population than an IRAK4 inhibitor.
  • the methylcellulose colony forming assay is a surrogate in vitro progenitor cell assay that allows for the evaluation of effect on progenitor cell function. Potency was found to be higher in the cultured cell line overexpressing the FLT3 double mutant (ITD, D835Y) versus the primary patient cell lines.
  • IRAK1/4 gene signature was previously described that is highly expressed in patients with myelomonocytic subtypes (M4 FAB) of adult and pediatric AML and with an antecedent MDS (JR Bennett et. al., Blood 2023 https://doi.org/10.1182/blood.2022018718) (FIGS.22A- 22B).
  • M4 FAB myelomonocytic subtypes
  • FIGS.22A- 22B JR Bennett et. al., Blood 2023 https://doi.org/10.1182/blood.2022018718)
  • VEN/AZA Venetoclax plus Azacitidine
  • DB1/ 147901903.2 250 A variety of primary patient cell lines were evaluated in colony forming assays in multiple sites. This assay measures leukemia stem cell progenitor cell function. When plated in methylcellulose, leukemic progenitor cells grow out and form colonies. Drugs are evaluated for inhibition of colony formation.
  • the methylcellulose colony forming assay is a surrogate in vitro progenitor cell assay that allows for the evaluation of effect on progenitor cell function.
  • AML patient cell lines are known to not grow well in methylcellulose.
  • the success rate for colony formation with patient cell lines is ⁇ 30%, which is what was observed in these studies.
  • Patient cell lines from FLT3 mutant or FLT3 WT AML patients were chosen.
  • the comparator for the FLT3 mutant cell lines is Gilteritinib/Xospata® and the comparator for the FLT3 WT cell lines is CA-4948/Emavusertib®. All patients were evaluated for known mutations at diagnosis.
  • Compound 8 was found to be active in all primary patient cell lines that could be evaluated (i.e., that formed colonies), and potent activity was observed regardless of patient mutational status. Compound 8 was found to be about equipotent to, or more potent than, gilteritinib in the FLT3 mutant setting. Compound 8 was found to have high potency in the colony forming assay regardless of whether the cell line has a PDGFR mutation. Where FAB classification was available, the M4 patients appeared to have the highest potency for Compound 8. Although not wishing to be limited by theory, it appears as though Compound 8 had high potency in FLT3 wild type patients with a TP53 mutation. There are currently no drugs that successfully treat these patients.
  • the IC50 for Compound 8 is ⁇ 250nM. This is more potent than what has been seen for Compound 8 in the THP-1 and MDSL cells. Complete inhibition of colony formation (a measure of leukemic progenitor cell function) was observed in all four cell lines with Compound 8. DB1/ 147901903.2 251 Compound 8 was found to potently inhibit leukemic stem cell progenitor function regardless of mutational status. Compound 8 was found to suppress colony formation in primary AML patient samples.
  • FIG.25A provides a comparison between % inhibition of colony formation (calculated as # treated colonies divided by # DMSO control colony growth) at 200 nM of Compound 8 across primary patient samples that are either wildtype (WT) or mutant for FLT3. No significant difference in response to inhibitor was observed between WT and FLT3 mutant samples, suggesting that similar drug doses can be used in both FLT3 WT and FLT3 mutant patient population (statistical analysis shown in FIG.25C).
  • FIG.25D provides a mutational status of the corresponding FLT3 WT patient AML primary bone marrow blasts. *Similar mutational profiles were seen in FLT3 mutant AML patient samples (data not shown).
  • Compound 8 exhibited superior potency and efficacy to gilteritinib in the FLT3-ITD (D835Y) xenograft model after QD oral dosing, with sufficient PK and oral bioavailability across multiple species to support QD or BID dosing in the clinic.
  • Compound 8 did not inhibit any of the major or minor cytochrome P450 enzymes at anticipated clinical concentrations and early indication from ongoing GLP toxicology studies suggest that it could be safely administered in humans.
  • Compound 8 was also found to have an optimized preclinical safety profile. Metabolism yielded no active metabolites and no CYP3A4 interactions.
  • Compound 8 was found to have an IC 50 of 7, 8, and >30 ⁇ M, respectively.
  • CV cardiovascular
  • Compound 8 was found to have no effect on beat rate, FPDc (heart rate-corrected field potential duration) ( ⁇ QTc (heart rate-corrected QT interval)) and no EADs (early after depolarizations (torsadogenic potential) in human iPSC-CMs (human induced-pluripotent stem cell cardiomyocytes) to 10 ⁇ M.
  • Compound 8 was also found to have no effect on QTc in guinea pig cardiovascular function (ECG) to high dose ⁇ 25x mouse AUCeff and yielded no changes in function or structure in rat echocardiography to high dose ⁇ 44x mouse AUC eff . There were also no ECG (QT, QTc, HR) or BP (blood pressure) findings in single dose GLP Dog CV study to high dose ⁇ 11x mouse AUCeff. 5 mg/kg of Compound 8 was administered to an animal AML model wherein animals treated with Compound 8 were found to have higher survival than control animals (33 treated animals survived versus 12 control animals) (FIG.26).
  • ECG guinea pig cardiovascular function
  • HR QT, QTc, HR
  • BP blood pressure
  • the animals treated with 5 mg/kg of DB1/ 147901903.2 252 Compound 8 also demonstrated higher survival than those treated with 35 mg/kg venetoclax. Additionally, animals treated with a combination of 5 mg/kg of Compound 8 and 35 mg/kg of venetoclax were found have higher survival than animals treated with either 5 mg/kg of Compound 8 alone (33 animals treated with Compound 8 alone survived versus 40 animals treated with the combination of Compound 8 and venetoclax) or 35 mg/kg of venetoclax alone (16 animals treated with venetoclax alone survived versus 40 animals treated with the combination of Compound 8 and venetoclax). Compound 8 demonstrated superior activity in vivo compared to benchmark compounds.
  • Compound 8 was found to prolong survival in mice xenografted with MOLM14 FLT3-ITD (D835Y) (FIG.27). Survival was maintained even after withdrawal of Compound 8. Superior efficacy in reducing AML burden of Compound 8 was also observed relative to either Gilteritinib and CA-4948 (data not shown). These results are not explained solely by difference in plasma levels or occupancy at FLT3-ITD D835Y. Compound 8 was also found to exhibit high oral bio-availability across multiple species. Compound 8 was found to have high oral bioavailability, moderate clearance, and good oral exposure in mouse, rat, and dog (Table 4). Table 4.
  • Crisaborole in the Pam3CSK4 stimulated PBMCs reduced IL-10 and TNF ⁇ in all three donors and additionally GM-CSF, IL-1 ⁇ , IL-17A and IL-23 in Donor 1. Cell viability was never compromised in any of the treatment conditions, therefore changes in cytokine levels are due to compound activity and not cell death.
  • TNF- ⁇ Tumor Necrosis Factor- alpha IL-1 ⁇ : Interleukin 1 beta IL-2: Interleukin 2 IL-4: Interleukin 4 IL-5 : Interleukin 5 IL-6: Interleukin 6 IL-10 : Interleukin 10 IL-12 : Interleukin 12 IL-13 : Interleukin 13 IL-17: interleukin 17 IL-23: interleukin 23 GM-CSF : Granulocyte macrophage colony stimulating factor DB1/ 147901903.2 254 IFN- ⁇ : Interferon gamma PBMC: peripheral blood mononuclear cells PBS: phosphate buffered saline FBS: fetal bovine serum mins: minutes r.p.m.
  • PBMCs DB1/ 147901903.2 255 Fresh blood was acquired from Bloodworks within 4 hours of collection. The donors were fully consented, and the blood was collected under IRB approval. The fresh blood samples were diluted with an equal volume of PBS + 2% FBS and layered over ficoll (Lymphoprep). The tubes were placed in the centrifuge at a speed of 1200 r.p.m. with the brake set to the “off” position. PBMCs were harvested from the buffy layer and transferred to a new tube and washed with PBS + 2% FBS.
  • test Articles and Controls Compound 8 was provided in solution (10 mM).
  • working stocks were made in RPMI + 10% HI-FBS to generate concentrations of 200 and 20 ⁇ M.
  • working stocks of Crisaborole were prepared at 200 ⁇ M. When added in at 1: 20 v/v, the desired test concentrations of Compound 8 were 10 and 1 ⁇ M and for Crisaborole was 10 ⁇ M.
  • a cell stock at 1.06 x 10 ⁇ 6/mL was mixed with equal volume of Pam3CSK4 at 20 ng/mL in RPMI + 10% HI- FBS (Pam3CSK4 final concentration at 10 ng/mL) and then 190 ⁇ L were added wells (100,000 cells/well).
  • a cell stock at 0.53 x 10 ⁇ 6/mL was prepared and 190 ⁇ L were added to wells (100,000 cells/well).
  • Test article Compound 8 and Crisaborole were prepared as described above, when 10 ⁇ L were added to 190 ⁇ L cells, the desired test concentrations were achieved.
  • PBS was added to the exterior wells of the 96-well plate to retain a high and equal humidity.
  • the content of cells and compounds were mixed and incubated at 37°C, 5% CO2 for 48 hours. After the 48-hour incubation, supernatants were harvested (170 ⁇ L) and divided between a well (95 ⁇ L) or an Eppendorf tube (75 ⁇ L). The supernatants in the wells were retained at -80 o C for backups and the supernatants in the Eppendorf tubes were coded and sent to Eve Technologies for cytokine analyses using the Luminex platform.
  • the cells were resuspended in PBS containing 2% FBS and stained with DAPI for cell viability assessed by flow cytometer.
  • Statistical Analyses of Data For each condition triplicate tests were performed. Cytokine analyses were assessed using the Luminex platform. Where mean and standard deviations are reported, the values used to generate these numbers did not include values that were below the limits of quantitation.
  • Compound 8 reduced IL-6 and TNF ⁇ from 10 – 0.1 ⁇ M, IL-8 and IL-10 from 10 – 0.3 ⁇ M and IL-17 at 10 ⁇ M.
  • Cell viability was never compromised in any of the treatment conditions, therefore changes in cytokine levels are due to compound activity and not cell death. There was no consistent trend in cytokine inhibition across donors with either stimulation below 1 ⁇ M Compound 8.
  • TNF- ⁇ Tumor Necrosis Factor-alpha IL-1 ⁇ : Interleukin 1 beta IL-2: Interleukin 2 IL-4: Interleukin 4 IL-5 : Interleukin 5 IL-6: Interleukin 6 IL-10 : Interleukin 10 IL-12 : Interleukin 12 IL-13 : Interleukin 13 IL-17: interleukin 17 IL-23: interleukin 23 GM-CSF : Granulocyte macrophage colony stimulating factor IFN- ⁇ : Interferon gamma PBMC: peripheral blood mononuclear cells DB1/ 147901903.2 268 PBS: phosphate buffered saline FBS: fetal bovine serum mins: minutes r.p.m.
  • PBMCs Fresh blood was acquired from Bloodworks within 4 hours of collection. The donors were fully consented, and the blood was collected under IRB. The fresh blood samples were diluted with an equal volume of PBS + 2% FBS and layered over ficoll (Lymphoprep). The tubes were placed in the centrifuge at a speed of 1200 r.p.m. with the brake set to the “off” position. PBMCs were harvested from the buffy layer and transferred to a new tube and washed with PBS + 2% FBS.
  • test Articles and Controls Compound 8 was provided in solution (10 mM).
  • working stocks were made in RPMI + 10% HI-FBS to generate concentrations of 200, 60, 20, 6, 2, 0.6, 0.2 and 0.06 ⁇ M. Additionally working stocks of Crisaborole were prepared at 200 ⁇ M.
  • a cell stock at 1.06 x 10 ⁇ 6/mL was mixed with equal volume of Dynabeads resuspended in RPMI + 10% HI-FBS (1:1 cells to beads ratio) and then 190 ⁇ L were added wells of a 96-well plate (100,000 cells/well).
  • a cell stock at 1.06 x 10 ⁇ 6/mL was mixed with equal volume of Pam3CSK4 at 20 ng/mL in RPMI + 10% HI- FBS (Pam3CSK4 final concentration at 10 ng/mL) and then 190 ⁇ L were added wells (100,000 cells/well).
  • test article Compound 8 and Crisaborole were prepared as described above, when 10 ⁇ L were added to 190 ⁇ L cells, the desired test DB1/ 147901903.2 270 concentrations were achieved.
  • PBS was added to the exterior wells of the 96-well plate to retain a high and equal humidity. The content of cells and compounds were mixed and incubated at 37°C, 5% CO 2 for 48 hours. After the 48-hour incubation, supernatants were harvested (170 ⁇ L) and divided between a well (95 ⁇ L) or an Eppendorf tube (75 ⁇ L).
  • the supernatants in the wells were retained at -80 o C for backups and the supernatants in the Eppendorf tubes were coded and sent to Eve Technologies for cytokine analyses using the Luminex platform.
  • the cytokines evaluated included GM-CSF, IFNy, IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL- 17A, IL-23 and TNF ⁇ .
  • the cells were resuspended in PBS containing 2% FBS and stained with DAPI for cell viability assessed by flow cytometer.
  • Statistical Analyses of Data For each condition, triplicate tests were performed.
  • Compound 8 did not induce any cytokines when compared to the unstimulated controls (Tables 13-15).
  • Tables 13-15 When Compound 8 was added to the PBMCs stimulated with Dynabeads, there was a significant reduction in multiple cytokines and again this varied between donors. However, there was a trend whereby if the Dynabeads induced cytokine secretion in a given donor, Compound 8 at 10 ⁇ M reduced this induction in all cases and additionally at 3 and 1 ⁇ M for a limited range of cytokines (IL-1 ⁇ in two of three donors and IL-6 in all donors). Crisaborole, known to reduce cytokine stimulation, was used an internal control in this study and again the extent of the reduction varied between donors.
  • Crisaborole reduced the amount with one exception of IL-8 where there was no reduction in any donor.
  • Compound 8 was added to the PBMCs stimulated with Pam3CSK4, there was a significant reduction in multiple cytokines and again this varied between donors.
  • co-culture of Pam3CSK4 and Compound 8 significantly reduced the cytokine induction.
  • Compound 8 reduced IL-8 and IL-10 from 10 – 0.3 ⁇ M and TNF ⁇ from 10 – 1 ⁇ M.
  • the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. In some embodiments, the terms “a” and “an” and “the” and similar references used in the context of describing a particular embodiment of the application (especially in the context of certain of the following claims) can be construed to cover both the singular and the plural. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range.
  • the phrases “such as,” “for example,” and “e.g.” mean “for example, but not limited to” in that the list following the term (“such as,” “for example,” or “e.g.”) provides some examples but the list is not necessarily a fully inclusive list.
  • the word “comprising” means that the items following the word “comprising” may include additional unrecited elements or steps; that is, DB1/ 147901903.2 294 “comprising” does not exclude additional unrecited steps or elements. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the application. In certain instances, sequences disclosed herein are included in publicly available databases, such as GENBANK ® and SWISSPROT.
  • the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.
  • Preferred embodiments of this application are described herein. Variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. It is contemplated that skilled artisans can employ such variations as appropriate, and the application can be practiced otherwise than specifically described herein.
  • IRAK1/4 dependency genes from FIG.4C (long IRAK1/4 gene signature) IRAK1/4 dependency genes PLS3 S1PR5 C10orf76 PCDHB13 HSBP1L1 WDFY4 C10orf91 PCDHB14 CDC42BPA GRK5 C15orf38 PCED1B PPP2R3A SREBF1 C2CD4C PCED1B-AS1 GNG12 STXBP5L C2CD5 PCSK5 PENK VARS2 C3orf18 PDLIM1 STC2 GAB2 CALHM2 PEAR1 DNAJC22 ZFP36L1 CAMK1D PFKP DB1/ 147901903.2 298 IRAK1/4 dependency genes SH3D19 CPNE7 CAPRIN2 PGAM1 GABRD HSPA2 CDH2 PGAM4 RAVER2 NAT8L CDHR1 PI15 ARHGEF26 DOK4 CEL PITX1 APBB2 IGF1R CEP72 PLEKHA8
  • IRAK1/4 dependency genes from FIG.10 (short IRAK1/4 gene signature) IRAK1/4 dependency genes KRAS COL27A1 DUSP5 COMTD1 SOX5 ARHGAP21 INPP5A ECHDC3 HMX2 PDLIM1 BRD9 PAOX TACC2 CAMK1D ZFYVE27 LPCAT1 AIFM2 SCAF11 LRMP ARSG ZNF438 DNAJB12 SLC38A1 PSTPIP2 FGD4 TUBGCP2 SLC12A7 VENTX GRK5 DNMBP ZMIZ1 AMIGO2 ANK3 JMJD1C ANO6 PCED1B ZNF622 ELK1 PRICKLE1 PCED1B ⁇ AS1 PWWP2B SFMBT2 CALHM2 BAG3 SFXN3 NRARP LINC00477 SLC29A3 DDIT4 NIM1K DB1/ 147901903.2 302 0 5 n O i e s W s IL

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Abstract

The present disclosure provides a method of treating an inflammatory disease or disorder, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS) in a subject, the method comprising administering to the subject a compound that inhibits IRAK1 and IRAK4. The present disclosure further provides a method of determining a subject with a disease/disorder that can be treated by the administration of a compound which inhibits IRAK1 and IRAK4.

Description

TITLE Multi-Cyclic IRAK1 and IRAK4 Inhibiting Compounds and Uses Thereof CROSS-REFERENCE TO RELATED APPLICATIONS The present application is an international application claiming priority to U.S. Provisional Application No.63/516,771, filed July 31, 2023, U.S. Provisional Application No. 63/578,386, filed August 24, 2023, and U.S. Provisional Application No.63/598,011, filed November 10, 2023, each of which is incorporated by reference herein in its entirety. GOVERNMENT RIGHTS This invention was made in the performance of a Cooperative Research and Development Agreement with the National Institutes of Health, an Agency of the Department of Health and Human Services. The Government of the United States has certain rights in this invention. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in.XML format and is hereby incorporated by reference in its entirety. The .XML copy, created on July 29, 2024, is named “130364-5012.xml” and is 18 KB in size. BACKGROUND IRAKs are a family of related kinases that operate at the nexus of multiple innate immune and inflammatory pathways implicated in myeloid malignancies. There is increasing interest in the role of the IRAK kinases as targets in the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) (reviewed in J Bennett and DT Starczynowski, Curr Opin Hematol 2022). IRAK1 and IRAK4 lie downstream of multiple receptors that stimulate the canonical NF-kB signaling pathway upstream of TRAF6 via the myddosome complex. While TRAF6 is necessary to preserve the tonic NF-kB signaling that is required for hematopoietic stem cell (HSC) homeostasis (J Fang et. al. Cell Reports 2018), overactivity of the NF-kB signaling pathway has been implicated in both MDS and AML (reviewed in MCJ Bosman et. al., Crit Rev Oncol/Hematol 2016; JJ Trowbridge and DT Starczynowski, J Exp Med 2021). The requirement for both IRAK1 and IRAK4 in this pathway has been explored using both genetic DB1/ 147901903.2 1 and pharmacologic technologies. The use of genetic loss-of-function approaches revealed that deletion and/or inhibition of IRAK4 results in a compensatory increase in IRAK1 protein and activation (data unpublished), suggesting that high potency antagonism of both kinases will be required for optimal inhibition of NF-kB-mediated transcriptional responses in disease- propagating MDS and AML cells. IRAK4 inhibitors have advanced into clinical trials for MDS and AML validating IRAK4 as a therapeutic target. Early data from these trials has been encouraging; however, the overall responses remain modest. MDS and AML exist along a continuous disease spectrum starting with early-stage MDS, which may progress to high-risk (HR) MDS and/or AML. AML is a heterogeneous malignancy characterized by suppression of normal hematopoiesis and overproduction of immature myeloid blast cells associated with a differentiation block. Most patients with HR-MDS and AML are not cured with available therapies, underscoring the urgent need for new therapeutic alternatives that will improve the clinical outcomes of these patients. Despite significant effort, the five-year relative survival of AML patients remains at only 25%. MDS and AML originate in hematopoietic stem and progenitor cells (HSPC, referred to as leukemic stem/progenitor cells [LSPC]) that acquire genetic and/or epigenetic abnormalities. A pool of LSPCs persist throughout the course of disease to replenish the bulk leukemic blast cells and contribute to treatment-related relapse when not eradicated. Recent therapies, such as Venetoclax with Azacytidine and Menin inhibitors, that target the LSPCs have shown improved clinical outcomes for patients with HR-MDS and AML. LSPCs also share cellular states and transcriptional programs with normal HSPCs, such as ones that maintain multi-potent self-renewal properties and prevent untimely differentiation. Like normal HSPCs, LSPCs have acquired an undifferentiated state that permits long-term expansion of progeny cells, properties which have been evaluated using surrogate in vitro progenitor assays (i.e., colony assays in methylcellulose) and in vivo hematopoietic transplantation models. Uncovering targetable signaling dependencies unique to LSPCs is critical to improve therapeutic responses in patients. It was recently reported that patient-derived LSPCs from HR- MDS and across various AML subtypes exhibit a high frequency of dysregulated immune and inflammatory pathways. Dysregulation of immune-related genes is observed in >50% of MDS and AML, and chronic innate immune pathway activation increases the risk of developing myeloid malignancies. Moreover, a significant number of genetic and molecular alterations in DB1/ 147901903.2 2 MDS and AML directly impinge on effectors of the Toll-like receptor (TLR) and Interleukin 1 receptor (IL-1R) pathways, both of which converge on a signaling complex operated by the interleukin-1 receptor associated kinases (IRAK): IRAK1, IRAK2, and IRAK4. In the context of normal immune cell biology, activation of TLRs or IL-1R leads to recruitment of the adaptor protein MyD88, which then nucleates an oligomeric signaling complex (Myddosome) that includes MyD88 and IRAK4. IRAK4 subsequently recruits and phosphorylates IRAK1 or IRAK2, which then induces multiple downstream effectors, including NF-kB and MAPKs. Chronic activation of this MyD88-IRAK canonical signaling axis is presumed to underly malignant hematopoiesis in MDS/AML, a theory that is partially supported by the discovery of activating mutations in MyD88 that cause spontaneous assembly of the Myddosome complex in lymphomas. Consequently, IRAK4 inhibitors and proteolysis targeting chimeric (PROTAC) small molecule degraders are undergoing evaluation in pre-clinical studies and early phase clinical trials for hematologic malignancies and inflammatory conditions. The IRAK4 kinase inhibitor PF-06650833 (Zimlovisertib) is being evaluated for chronic inflammatory disorders, while CA-4948 (Emavusertib) is being evaluated in hematologic malignancies, including lymphoma, HR- and low-risk (LR)-MDS, and refractory/relapsed AML. The IRAK4 PROTACs, KT-474 and KT-413, are being evaluated in immuno-inflammatory disease and MyD88-mutant lymphomas, respectively. Safety data from these trials have revealed minimal on-target toxicity nor adverse effects, suggesting that targeting IRAK4 will have an acceptable safety profile and tolerability. Initial results from the early phase trials in HR-MDS and AML with CA-4948 showed complete or partial response rates of ~40% and additional patients having reductions in leukemic blast counts. Interestingly, 40% of AML patients with spliceosome mutations reached a complete response (CR) or CR with partial hematologic recovery (CRh), while 57% of HR-MDS patients achieved a CR. These clinical observations support the recent findings that mutations in the splicing factors U2AF1 and SF3B1 directly induce hypermorphic IRAK4 isoforms and active innate immune signaling in MDS and AML. The data emerging from the ongoing clinical studies suggest that IRAK4 is a relevant target in hematologic malignancies. However, the magnitude of clinical responses appears to depend on genetic background and suggests inadequacy of IRAK4 inhibitors as monotherapy. Thus, a better understanding of IRAK4 signaling is necessary to refine therapeutic strategies targeting dysregulated innate immune and inflammatory signaling in hematologic malignancies. DB1/ 147901903.2 3 The present disclosure addresses this unmet need. SUMMARY OF THE DISCLOSURE In one aspect, the present disclosure provides a method of treating an inflammatory disease or disorder, or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), in a subject in need thereof, the method comprising administering to the subject Compound 8: or a salt, ester, solvate, optical of an isomer thereof. In one
Figure imgf000005_0001
embodiment, the inflammatory disease or disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis. In one embodiment, the AML is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML, or the MDS is MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, or MDS with a splicing factor mutation, optionally wherein the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1, SRSF2, SF3B1, or ZRSR2. In one embodiment, the subject has AML and the subject has a gene mutation in one or more of FLT3, TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, JAK2, ASXL1, ABL1, ATRX, BCORL1, KDM6A, PTPN11, TP53, CBL, CEBPA, FBXW7, HRAS, NRAS, IDH1, IDH2, NRAS, PDGFRA, SF3B1, ETV6, PHF6, GNAS, KRAS, NOTCH1, STAG2, SETBP1, GATA1, GATA2, WT1, SRSF2, GNAS, CEBPA, CALR, MPL, BCL11A, ATM, CTCF, U2AF1, TYK2, FBX, RUI, RAD21, or MLL3, or the subject has MDS and the subject has a gene mutation in one or more of DB1/ 147901903.2 4 U2AF1, FLT3, ASXL1, BCORL1, BRAF, CBL, CDKN2A, DNMT3A, FBXW7, GATA2, IDH2, KRAS, NOTCH1, NRAS, PDGFRA, PTEN, PTPN11, TET2, TP53, EZH2, HRAS, KIT, MPL, PHF6, RUNX1, WT1, ABL1, CEBPA, ETV6, IDH2, KDM6A, KIT, KRAS, PTEN, RUNX1, SF3B1, or ZRSR2. In one embodiment, Compound 8 has an IRAK1 IC50 of less than about 40 nM, optionally less than about 5 nM, and/or a FLT3 IC50 of less than about 2.5 nM. In one embodiment, Compound 8 has an IRAK4:IRAK1 inhibitory potency ratio of less than about 40. In one embodiment, the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes and/or decreased expression of one or more IRAK1/4-associated genes. In one embodiment, the subject in need thereof has elevated expression and/or decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject. In one embodiment, the subject in need thereof has elevated expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DB1/ 147901903.2 5 DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, DB1/ 147901903.2 6 SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395, optionally the subject in need thereof has elevated expression of one or more IRAK1/4- associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. In one embodiment, the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, DB1/ 147901903.2 7 TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, DB1/ 147901903.2 8 PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395, optionally the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. In one embodiment, upon administration to the subject, Compound 8 decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject, and/or increases the expression of one or more IRAK1/4-associated genes found to be decreased in the subject. In one embodiment, the administration of Compound 8 decreases the expression of the one or more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of the one or more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8. In one embodiment, the administration of Compound 8 decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control DB1/ 147901903.2 9 subject, and/or increases the expression of one or more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject. In one embodiment, upon administration to the subject, Compound 8 decreases the expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, DB1/ 147901903.2 10 AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, DB1/ 147901903.2 11 LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject, optionally the compound decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. In one embodiment, upon administration to the subject, Compound 8 increases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, DB1/ 147901903.2 12 ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, DB1/ 147901903.2 13 THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject, optionally wherein the compound increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. In one embodiment, the subject in need thereof has elevated expression of one or more NFκB- associated genes, and/or decreased expression of one or more NFκB-associated genes. In one embodiment, the subject in need thereof has elevated expression of one or more NFκB- associated genes compared to a healthy control subject, and/or decreased expression of one or more NFκB-associated genes compared to a healthy control subject. In one embodiment, the subject in need thereof has elevated expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, DB1/ 147901903.2 14 CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. In one embodiment, the subject in need thereof has decreased expression of one or more NFκB- DB1/ 147901903.2 15 associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, DB1/ 147901903.2 16 REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. In one embodiment, upon administration to the subject, Compound 8 decreases the expression of one or more NFκB-associated genes found to be elevated in the subject, and/or increases the expression of one or more NFκB-associated genes found to be decreased in the subject. In one embodiment, the administration of Compound 8 decreases the expression of the one or more NFκB-associated genes found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of the one or more NFκB-associated genes found to be decreased in the subject before the administration of Compound 8. In one embodiment, Compound 8 decreases the expression of one or more NFκB-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more NFκB- associated genes found to be decreased in the subject compared to a healthy control subject. In one embodiment, upon administration to the subject, Compound 8 decreases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, DB1/ 147901903.2 17 CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. In one embodiment, upon administration to the subject, Compound 8 increases the expression of one or DB1/ 147901903.2 18 more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, DB1/ 147901903.2 19 RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. In one embodiment, the subject in need thereof has elevated secretion of one or more cytokines, optionally wherein the one or more cytokines are selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ. In one embodiment, the subject in need thereof has elevated secretion of one or more cytokines compared to a healthy control subject, optionally wherein the one or more cytokines are selected from: TNF-α, IL-1 β, IL-2, IL- 4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ. In one embodiment, Compound 8 decreases the secretion of one or more cytokines found to be elevated in the subject, optionally wherein the compound decreases the secretion of one or more cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM- CSF, and IFN-γ in the subject. In one embodiment, the administration of Compound 8 decreases the expression of the one or more cytokines found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of the one or more cytokines found to be decreased in the subject before the administration of Compound 8. In one embodiment, upon administration to the subject, Compound 8 decreases the expression of one or more cytokines found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more cytokines found to be decreased in the subject compared to a healthy control subject. In yet another aspect, when Compound 8 is used in any of the methods described above, Compound 8 is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. In one embodiment, Compound 8 DB1/ 147901903.2 20 provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject, optionally wherein the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. In one embodiment, in any of the methods described above, the administration of Compound 8 comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration; and/or Compound 8 is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight; and/or Compound 8 is administered to the subject in a dosage of from about 0.35 mg to about 70,000 mg; and/or Compound 8 is administered to the subject daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once a week, twice a month, or once a month. In one embodiment, in any of the methods described above, Compound 8 treats the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject during the time period that the compound is administered to the subject. In one embodiment, in any of the methods described above, Compound 8 continues to treat the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject after the administration is stopped, optionally wherein Compound 8 continues to treat the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped. In one embodiment, in any of the methods described above, the method further comprises administering to the subject one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, DB1/ 147901903.2 21 an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor; optionally comprising administering to the subject at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof; and/or the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, or acalabrutinib or a pharmaceutically acceptable salt thereof; and/or the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof; and/or the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof; and/or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject; optionally wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof; optionally wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. DB1/ 147901903.2 22 In yet another aspect, the present disclosure provides a method of determining whether a subject with a disease or disorder selected from an inflammatory disease or disorder, and a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), can be treated by administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, the method comprising: determining whether the subject has an elevated expression of one or more IRAK1/4-associated genes and/or a decreased expression of one or more IRAK1/4-associated genes, wherein the IRAK1/4-associated genes are selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, DB1/ 147901903.2 23 PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, DB1/ 147901903.2 24 ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395; optionally wherein the IRAK1/4-associated genes are selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. In one embodiment, the subject has elevated expression of one or more IRAK1/4-associated genes compared to a healthy control subject and/or a decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject. In one embodiment, the subject in need thereof has an elevated expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, DB1/ 147901903.2 25 ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, DB1/ 147901903.2 26 PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395; optionally wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. In one embodiment, the subject in need thereof has a decreased expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, DB1/ 147901903.2 27 TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, DB1/ 147901903.2 28 LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395, optionally wherein the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. In one embodiment, Compound 8 decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject, and/or increases the expression of one or more IRAK1/4- associated genes found to be decreased in the subject. In one embodiment, Compound 8 decreases the expression of the one or more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of the one DB1/ 147901903.2 29 or more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8. In one embodiment, Compound 8 decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject. In one embodiment, Compound 8 decreases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, DB1/ 147901903.2 30 TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, DB1/ 147901903.2 31 CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject; optionally wherein the compound decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. In one embodiment, Compound 8 increases the expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, DB1/ 147901903.2 32 TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, DB1/ 147901903.2 33 SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject; optionally wherein the compound increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. In yet another aspect, the present disclosure relates to a method of determining whether a subject with a disease or disorder selected from an inflammatory disease or disorder, and a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), can be treated by the administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, the method comprising: determining whether the subject has an elevated expression of one or more NFκB-associated genes, and/or a decreased expression of one or more NFκB-associated genes, wherein the NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, DB1/ 147901903.2 34 CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, DB1/ 147901903.2 35 TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. In one embodiment, the subject has elevated expression of one or more NFκB-associated genes compared to a healthy control subject and/or a decreased expression of one or more IRAK1/4- associated genes compared to a healthy control subject. In one embodiment, subject in need thereof has an elevated expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, DB1/ 147901903.2 36 MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. In one embodiment, the subject in need thereof has a decreased expression of one or more NFκB- associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. DB1/ 147901903.2 37 FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. In one embodiment, Compound 8 decreases the expression of one or more NFκB-associated genes found to be elevated in the subject, and/or increases the expression of one or more NFκB- associated genes found to be decreased in the subject. In one embodiment, Compound 8 decreases the expression of one or more NFκB-associated genes found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of one or more DB1/ 147901903.2 38 NFκB-associated genes found to be decreased in the subject before the administration of Compound 8. In one embodiment, Compound 8 decreases the expression of one or more NFκB- associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more NFκB-associated genes found to be decreased in the subject compared to a healthy control subject. In one embodiment, Compound 8 decreases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, DB1/ 147901903.2 39 NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. In one embodiment, Compound 8 increases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, DB1/ 147901903.2 40 GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. In another aspect, the present disclosure provides a method of determining whether a subject with a disease or disorder selected from an inflammatory disease or disorder, or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), can be treated by the administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, the method comprising: determining whether the subject has DB1/ 147901903.2 41 an elevated secretion of one or more cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ. In one embodiment, the subject has elevated expression of one or more cytokines compared to a healthy control subject and/or a decreased expression of one or more cytokines compared to a healthy control subject. In one embodiment, any of the methods described above further comprise administering to the subject Compound 8:
Figure imgf000043_0001
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In one embodiment, the inflammatory disease or disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis. In one embodiment, the AML is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML, optionally wherein the subject has AML and the subject has a gene mutation in one or more of FLT3, TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, JAK2, ASXL1, ABL1, ATRX, BCORL1, KDM6A, PTPN11, TP53, CBL, CEBPA, FBXW7, HRAS, NRAS, IDH1, IDH2, NRAS, PDGFRA, SF3B1, ETV6, PHF6, GNAS, KRAS, NOTCH1, STAG2, SETBP1, GATA1, GATA2, WT1, SRSF2, GNAS, CEBPA, CALR, MPL, BCL11A, ATM, CTCF, U2AF1, TYK2, FBX, RUI, RAD21, or MLL3; and/or the MDS is MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2, optionally wherein the subject has MDS and has a gene mutation in U2AF1, FLT3, ASXL1, BCORL1, BRAF, CBL, CDKN2A, DNMT3A, FBXW7, GATA2, IDH2, KRAS, NOTCH1, NRAS, PDGFRA, PTEN, PTPN11, TET2, TP53, EZH2, HRAS, KIT, MPL, PHF6, RUNX1, WT1, ABL1, CEBPA, ETV6, IDH2, KDM6A, KIT, DB1/ 147901903.2 42 KRAS, PTEN, RUNX1, SF3B1, or ZRSR2; and/or optionally wherein the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1, SRSF2, SF3B1, or ZRSR2. In one embodiment, Compound 8 has an IRAK1 IC50 of less than about 40 nM, optionally an IRAK4 IC50 of less than about 5 nM, and/or an FLT3 IC50 of less than about 2.5 nM. In one embodiment, Compound 8 has IRAK4:IRAK1 inhibitory potency ratio of less than about 40. In one embodiment, Compound 8 is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. In one embodiment, Compound 8 provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject, optionally wherein the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. In one embodiment, in any of the methods described above, the administration of Compound 8 comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration; and/or Compound 8 is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight; and/or Compound 8 is administered to the subject in a dosage of from about 0.35 mg to about 70,000 mg; and/or Compound 8 is administered to the subject daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once a week, twice a month, or once a month. In one embodiment, in any of the methods described above, Compound 8 treats the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject during the time period that the compound is administered to the subject. In one embodiment, in any of the methods described above, Compound 8 continues to treat the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject after the administration is stopped, optionally Compound 8 continues to treat the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped. In one embodiment, in any of the methods described above, the method further comprises administering to the subject one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a DB1/ 147901903.2 43 BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF- 1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor; optionally comprising administering to the subject at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof; and/or the BTK inhibitor is ibrutinib or acalabrutinib or a pharmaceutically acceptable salt of any one thereof; and/or the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof; and/or the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof; and/or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject; optionally the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof; DB1/ 147901903.2 44 optionally wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 depicts that the NFkB potency of Compounds 1-13, Compound 15, and comparative compounds correlates with their IRAK1 potency. FIG.2 depicts that the NFkB potency of Compounds 1-13, Compound 15, and comparative compounds correlates with their IRAK4 potency. FIG.3 depicts colony forming assays demonstrating that the NFkB potency of Compounds 1-13 and Compound 15 correlates with their MDSL CFC potency. FIG.4 depicts colony forming assays demonstrating that the NFkB potency of Compounds 1-13 and Compound 15 correlates with their THP-1 CFC potency. FIG.5 depicts the kinase profile of comparative compounds with their PAM and IL1β IC50. FIG.6A depicts Compound 14 and Compound 15. FIG.6B depicts the kinase profile of Compound 14 and Compound 15 with their PAM and IL1β IC50. FIG.7 depicts the kinase profile of Compound 2, Compound 7, and Compound 8 with their PAM and IL1β IC50. FIGS.8A-8B depict the MS methods used in Example 2. The MS is the standard curve quantitation values demonstrating the range of quants applicable from the qualified assay using recombinant proteins assessed via the method. FIG.8A depicts IRAK1/4 expression analysis by IP-MS. FIG.8B depicts hybrid LCMS. FIG.9 demonstrates that Compound 8 is a highly potent and selective IRAK1/IRAK4/panFLT3 inhibitor. FIG.10 demonstrates that dual IRAK1/4 inhibition drives NF-κB signaling, wherein complete antagonism of signaling through both receptor pathways is only seen with the IRAK1/4 inhibitor Compound 8. DB1/ 147901903.2 45 FIGS.11A-11C demonstrate that Compound 8 suppresses NF-κB and IRAK1/4- dependent signaling in AML cells. FIG.11A is a principal component analysis (PCA) plot showing the variation between the samples in THP-1 cells. FIG.11B is a plot depicting the relative expression of NF-κB target genes by their Z-score (blue downregulated genes, red upregulated genes). FIG.11C is a plot depicting the relative expression of IRAK1/4 dependency genes by their Z-score (blue downregulated genes, red upregulated genes). FIG.12 is a chart depicting differentially expressed genes (DEGs) for different concentrations of Compound 8 and CA-4948 (emavusertib) calculated by comparison against control samples. FIGS.13A-13C are charts of DEGs versus drug concentration. FIG.13A is a chart of control versus 1 µM Compound 8 DEGs. FIG.13B is a chart of control versus 5 µM Compound 8 DEGs. FIG 13C is a chart of control versus 10 µM CA-4948 DEGs. FIGS.14A-14C provides charts and Venn diagrams of common DEGs for different drugs/concentrations. FIG.14A is a chart and Venn diagram of common DEGs between 10 µM CA-4948 and 1 µM Compound 8. FIG.14B is a chart and Venn diagram of common DEGs between 10 µM CA-4948 and 5 µM Compound 8. FIG.14C is a chart and Venn diagram of common DEGs between 1 µM Compound 8 and 5 µM Compound 8. FIGS.15A-15B provide canonical NF-κB target genes. FIG.15A is a chart of canonical NfκB target genes for different concentrations of Compound 8 and CA-4948. FIG.15B is a plot of control versus 5 µM Compound 8 canonical NF-κB target genes. FIGS.16A-16B provide signature genes on Compound 8 (by fold change). FIG.16A is a chart of signature genes for different concentrations of Compound 8 and CA-4948. FIG.16B is a plot of control versus 5 µM Compound 8. FIG.17 depicts the short IRAK1/4 gene signature for Compound 8 (by Z-score). FIG.18 is a chart of FLT3 wildtype THP-1 (left) and MDSL (right) cultured cells treated with DMSO and different concentrations of CA-4948 or Compound 8. FIGS.19A-19F demonstrate that Compound 8 impairs leukemic colony formation in FLT3 wild type primary patient cells. FIG.19A depicts colony formation data in FLT3 wild type AML(33766) patient cells. FIG.19B depicts colony formation data in FLT3 wild type MDS(3328) patient cells. FIG.19C depicts colony formation data in FLT3 wild type AML(2702) patient cells. FIG.19D depicts colony formation data in FLT3 wild type DB1/ 147901903.2 46 AML(3438) patient cells. FIG.19E depicts colony formation data in FLT3 wild type AML(2456) patient cells. FIG.19F depicts colony formation data in FLT3 wild type AML(2239) patient cells. FIG.20 is a chart of FLT3 mutant MOLM14 (D835Y) cultured cells treated with DMSO and different concentrations of gilteritinib, CA-4948 or Compound 8. FIGS.21A-21B demonstrate that Compound 8 impairs leukemic colony formation in FLT3 mutant primary patient cells. FIG.21A depicts colony formation data in FLT3 mutant AML(3930) patient cells. FIG.21B depicts colony formation data in FLT3 mutant AML(2228) patient cells. FIGS.22A-22B depict the creation of an IRAK1/4 signature (FIG.22A) and the analysis of the IRAK1/4 signature in patients (FIG.22B). FIGS.23A-23I depict the analysis of primary AML blast colony forming assays of FLT3 wildtype patients. FIGS.24A-24G depict the analysis of primary AML blast colony forming assays of FLT3 mutant patients. FIGS.25A-25D demonstrate that Compound 8 potently inhibits leukemic stem cell progenitor function regardless of mutational status. FIG.25A is a comparison between % inhibition of colony formation at 200 nM of Compound 8 across primary patient samples that are either wildtype or mutant for FLT3. No significant difference in response to inhibitor was seen between WT and FLT3 mutant samples. FIG.25B is a CFU comparison (WT vs mutant) and provides an estimation plot showing no significant difference between the two populations. FIG.25C provides the statistical analysis for the data shown in FIG.25A and FIG.25B. FIG. 25D is a chart of the mutational status of the corresponding FLT3 WT patient AML primary bone marrow blasts. *Similar mutational profiles were seen in FLT3 mutant AML patient samples (data not shown). FIG.26 provides a graph and a table demonstrating that the survival of an AML animal model is increased when the animal is treated with Compound 8 or venetoclax compared to a control animal. Survival is further increased when the animal is treated with a combination of Compound 8 and venetoclax. FIG.27 provides a graph demonstrating that Compound 8 prolongs survival in mice xenografted with MOLM14 FLT3-ITD (D835Y) compared to gilteritinib and CA-4948. DB1/ 147901903.2 47 FIGS.28A-28X demonstrate that Compound 8 inhibits innate and adaptive cytokine production. Healthy donor PBMCs were obtained for n=3 donors. To obtain this data, the cells were co-incubated for 48 hrs with stimulants +/- Compound 8 at 1 µM and 10 µM. Innate signaling stim is PAM3CSK4 at 10 ng/mL. Adaptive immune signaling stim is CD3-CD28 Dynabeads at 1:1 ratio (beads:cell). Crisaborole is a control inhibitor that inhibits most inflammatory cytokines. The supernatants were collected and analyzed for GM-CSF, IFNγ, IL- 1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70 (no changes), IL-13, IL-17A, IL-23, and TNFα. DETAILED DESCRIPTION The following related applications are incorporated by reference herein in their entirety, and for all purposes: International Publication No. WO 2018081738, TREATMENT OF DISEASES ASSOCIATED WITH ACTIVATED IRAK, filed October 30, 2017; U.S. Publication No.2021/0292843, TREATMENT OF DISEASES ASSOCIATED WITH ACTIVATED IRAK, filed April 4, 2019; International Publication No. WO 2014190163, Combination Therapy for MDS, filed May 22, 2014; U.S. Patent No.9,168,257, Combination Therapy for MDS, issued October 27, 2015; U.S. Patent No.9,504,706, Combination Therapy for MDS, issued November 29, 2016; U.S. Patent No.9,855,273, Combination Therapy for MDS, issued January 2, 2018; International Publication No. WO 2018038988, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed August 16, 2017; U.S. Patent No.11,254,667, Substituted imidazo[1,2-a]pyridines as IRAK 1/4 and FLT3 inhibitors, issued February 2, 2022; U.S. Publication No.2022/0213094, Substituted Imidazo[l,2-a]-pyridines as IRAK 1/4 and FLT3 Inhibitors, filed January 4, 2022; U.S. Publication No.2020/0199123, Substituted imidazo[1,2-a]pyridines as IRAK 1/4 and FLT3 inhibitors, filed February 28, 2020; U.S. Publication No.2022/0235042, Substituted Imidazo[l,2- a]-pyridines as IRAK 1/4 and FLT3 Inhibitors, filed January 28, 2022; International Publication No. WO 2020252487, Rational therapeutic targeting of oncogenic immune signaling states in myeloid malignancies via the ubiquitin conjugating enzyme UBE2N, filed June 15, 2020; International Publication No. WO 2022026935, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed July 31, 2021; International Publication No. WO 2022140647, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed December 23, 2021; International Publication No. WO 2023009833, Multi-Cyclic IRAK and DB1/ 147901903.2 48 FLT3 Inhibiting Compounds and Uses Thereof, filed July 29, 2022; International Patent Application No. PCT/US2023/068520, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed June 15, 2023; International Patent Application No. PCT/US2023/068897, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed June 22, 2023; International Patent Application No. PCT/US2023/071435, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed August 1, 2023; International Patent Application No. PCT/US2023/034438, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed October 4, 2023; U.S. Patent Application No.18/293,109, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed January 29, 2024; and International Patent Application No. PCT/US2024/014038, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed February 1, 2024. While embodiments encompassing the general disclosed concepts may take diverse forms, various embodiments will be described herein, with the understanding that the present disclosure is to be considered merely exemplary, and the general disclosed concepts are not intended to be limited to the disclosed embodiments. Some embodiments of the disclosure include disclosed compounds. Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the disclosed compound. Still other embodiments of the disclosure include compositions for treating, for example, certain diseases using the disclosed compounds. Some embodiments include methods of using the disclosed compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating. Further embodiments include methods for making the disclosed compound. Yet further embodiments include methods for determining whether a particular patient is likely to be responsive to such treatment with the disclosed compounds and compositions. Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-. DB1/ 147901903.2 49 As used herein, in relation to the compounds of the disclosure, the term “attached” signifies a stable covalent bond, certain preferred points of attachment being apparent to those of ordinary skill in the art. As used herein (unless otherwise specified), the term “alkyl” means a monovalent, straight or branched hydrocarbon chain, which can be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). For example, the terms “C1-C7 alkyl” or “C1-C4 alkyl” refer to straight- or branched-chain saturated hydrocarbon groups having from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7), or 1 to 4 (e.g., 1, 2, 3, or 4), carbon atoms, respectively. Examples of C1-C7 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n- pentyl, s-pentyl, n-hexyl, and n-septyl. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl. As used herein (unless otherwise specified), the term “alkenyl” means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) double bonds. Double bonds can occur in any stable point along the chain and the carbon-carbon double bonds can have either the cis or trans configuration. For example, this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, l-pentenyl-3-cyclohexenyl, and the like. Similarly, “heteroalkenyl” refers to heteroalkyl having one or more double bonds. Further examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2- propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl. As used herein (unless otherwise specified), the term “alkynyl” means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) triple bonds and that also may optionally include one or more (e.g.1, 2, 3, or 4) double bonds in the chain. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. As used herein (unless otherwise specified), the term “alkoxy” means any of the above alkyl, alkenyl, or alkynyl groups which is attached to the remainder of the molecule by an DB1/ 147901903.2 50 oxygen atom (alkyl-O-). Examples of alkoxy groups include, but are not limited to, methoxy (sometimes shown as MeO-), ethoxy, isopropoxy, propoxy, and butyloxy. The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, or alkynyl group, as exemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the compounds disclosed herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. As used herein (unless otherwise specified), the term “cycloalkyl” means a monovalent, monocyclic or bicyclic, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered hydrocarbon group. The rings can be saturated or partially unsaturated. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicycloalkyls (e.g., bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds). For a monocyclic cycloalkyl, the ring is not aromatic. For a bicyclic cycloalkyl, if one ring is aromatic, then the other is not aromatic. For a bicyclic cycloalkyl, one or both rings can be substituted. The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized, and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) O, N, P, S, and Si can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH 2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH- N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3. Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, DB1/ 147901903.2 51 heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. As used herein (unless otherwise specified), the term “halogen” or “halo” means monovalent Cl, F, Br, or I. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like. As used herein (unless otherwise specified), the term “aryl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 member aromatic hydrocarbon group and also means polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. For an aryl that is bicyclic, one or both rings can be substituted. As used herein (unless otherwise specified), the term “heteroaryl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon group, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen, oxygen, or sulfur atom, and the monocyclic or bicyclic ring system is aromatic. Heteroaryl groups (or rings) can contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple DB1/ 147901903.2 52 rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Examples of heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, 1H-pyrazol-4-yl, 1-Me-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 3,5-dimethylisoxazolyl, 1H- pyrrol-3-yl, 3,5-di-Me-pyrazolyl, and 1H-pyrazol-4-yl. For a bicyclic heteroaryl, if one ring is aryl, then the other is heteroaryl. For a bicyclic heteroaryl, one or both rings can have one or more hetero atoms. For a bicyclic heteroaryl, one or both rings can be substituted. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Accordingly, the term "aryl" can represent an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e. g.3-indolyl, 4-imidazolyl). The aryl substituents are independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, C1-16alkyl, arylC1-16alkyl, C0-16alkyloxyC0-16alkyl, arylC0-16alkyloxyC0-16alkyl, C0-16alkylthioC0-16alkyl, arylC0-16alkylthioC0-16alkyl, C0- 16alkylaminoC0-16alkyl, arylC0-16alkylaminoC0-16alkyl, di(arylC1-16alkyl)aminoC0-16alkyl, C1- 16alkylcarbonylC0-16alkyl, arylC1-16alkylcarbonylC0-16alkyl, C1-16alkylcarboxyC0-16alkyl, arylC1- 16alkylcarboxyC0-16alkyl, C1-16alkylcarbonylaminoC0-16alkyl, arylC1-16alkylcarbonylaminoC0- 16alkyl,-C0-16alkylCOOR4, -C0-16alkylCONR5R6 wherein R4, R5 and R6 are independently selected from hydrogen, C1-C11alkyl, arylC0-C11alkyl, or R5 and R6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with or without one C1-16alkyl, arylC0-C16alkyl, or C0-Cl16alkylaryl substituent. Aryl includes but is not limited to pyrazolyl and triazolyl. DB1/ 147901903.2 53 For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the terms “arylalkyl,” “aralkyl” and the like are meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like), or a sulfur atom. Accordingly, the terms "arylalkyl" and the like (e.g. (4- hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represents an aryl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms. The terms “cycloalkyl” and “heterocycloalkyl”, also referred to as “heterocyclyl”, by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. As used herein (unless otherwise specified), the term “heterocycloalkyl” or “heterocyclyl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen atom, oxygen atom, or sulfur atom, and the monocyclic or bicyclic ring system is not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, tetrahydropyran, pyrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, or pyrrolidin-4-yl), piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl, piperazin-3- yl, or piperazin-4-yl), piperidinyl (e.g., piperadin-1-yl, piperadin-2-yl, piperadin-3-yl, or piperadin-4-yl), and morpholinyl (e.g., morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, or morpholin-4-yl,). For a bicyclic heterocyclyl, if one ring is aromatic (e.g., monocyclic aryl or heteroaryl), then the other ring is not aromatic. For a bicyclic heterocyclyl, one or both rings can have one or more hetero atoms. For a bicyclic heterocyclyl, one or both rings can be substituted and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another DB1/ 147901903.2 54 substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. As used herein (unless otherwise specified), the term “hetero atom” means an atom selected from nitrogen atom, oxygen atom, or sulfur atom. As used herein (unless otherwise specified), the terms “hydroxy” or “hydroxyl” means a monovalent -OH group. The term “acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. The term “alkylsulfonyl,” as used herein, means a moiety having the formula -S(O2)-R', where R' is an alkyl group as defined above. R' can have a specified number of carbons (e.g., “C1-C4 alkylsulfonyl”). The term "carbonyloxy" represents a carbonyl group attached through an oxygen bridge. In the above definitions, the terms "alkyl" and "alkenyl" can be used interchangeably in so far as a stable chemical entity is formed, as would be apparent to those skilled in the art. The term “linker” refers to attachment groups interposed between substituents. In some embodiments, the linker includes amido (-CONH-Rn or -NHCO-Rn), thioamido (-CSNH-Rn or -NHCS-Rn), carboxyl (-CO2-Rn or -OCORn), carbonyl (-CO-Rn), urea (-NHCONH-Rn), thiourea (-NHCSNH-Rn), sulfonamido (-NHSO2-Rn or -SO2NH-Rn), ether (-O-Rn), sulfonyl (-SO2-Rn), sulfoxyl (-SO-Rn), carbamoyl (-NHCO2-Rn or -OCONH-Rn), or amino (-NHRn) linking moieties. Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and “heteroaryl”, and so forth) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided herein. As used herein (unless otherwise specified), the term “substituted” (e.g., as in substituted alkyl) means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be replaced by one or more non-hydrogen substituents selected from the specified options. The replacement can occur at one or more positions. The term “optionally substituted” DB1/ 147901903.2 55 means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be, but is not required to be substituted. A “substituent group,” as used herein, means a non-hydrogen substituent group that may be, and preferably is, a group selected from the following moieties: (A) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), CONH2, - CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluorinated alkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from: (i) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), CONH2, - CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluorinated alkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from: (a) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), CONH2, - CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluorinated alkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from: -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), CONH2, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluorinated alkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, DB1/ 147901903.2 56 unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl. A “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group, e.g., selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C4-C8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4-8-membered heterocycloalkyl. A “lower substituent” or “lower substituent group,” as used herein, means a group, e.g., selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C5-C7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5-7-membered heterocycloalkyl. The term “about” used in the context of a numeric value indicates a range of +/- 10% of the numeric value, unless expressly indicated otherwise. Some compounds of the disclosure can have one or more chiral centers and can exist in and be isolated in optically active and racemic forms, for any of the one or more chiral centers. Some compounds can exhibit polymorphism. The compounds of the present disclosure (e.g., Formula I) encompass any optically active, racemate, stereoisomer form, polymorphism, or mixtures thereof. If a chiral center does not provide an indication of its configuration (i.e., R or S) in a chemical structure, it should be considered to represent R, S or a racemate. As used herein, the term “sample” encompasses a sample obtained from a subject or patient. The sample can be of any biological tissue or fluid. Such samples include, but are not limited to, sputum, saliva, buccal sample, oral sample, blood, serum, mucus, plasma, urine, blood cells (e.g., white cells), circulating cells (e.g. stem cells or endothelial cells in the blood), tissue, core or fine needle biopsy samples, cell-containing body fluids, free floating nucleic acids, urine, stool, peritoneal fluid, and pleural fluid, tear fluid, or cells therefrom. Samples can also include sections of tissues such as frozen or fixed sections taken for histological purposes or DB1/ 147901903.2 57 microdissected cells or extracellular parts thereof. A sample to be analyzed can be tissue material from a tissue biopsy obtained by aspiration or punch, excision or by any other surgical method leading to biopsy or resected cellular material. Such a sample can comprise cells obtained from a subject or patient. In some embodiments, the sample is a body fluid that include, for example, blood fluids, serum, mucus, plasma, lymph, ascitic fluids, gynecological fluids, or urine but not limited to these fluids. In some embodiments, the sample can be a non- invasive sample, such as, for example, a saline swish, a buccal scrape, a buccal swab, and the like. As used herein, “blood” can include, for example, plasma, serum, whole blood, blood lysates, and the like. As used herein, the term “assessing” includes any form of measurement, and includes determining if an element is present or not. The terms “determining,” “measuring,” “evaluating,” “assessing,” “analyzing,” and “assaying” can be used interchangeably and can include quantitative and/or qualitative determinations. As used herein, the term “monitoring” with reference to a type of cancer refers to a method or process of determining the severity or degree of the type of cancer or stratifying the type of cancer based on risk and/or probability of mortality. In some embodiments, monitoring relates to a method or process of determining the therapeutic efficacy of a treatment being administered to a patient. As used herein, “outcome” can refer to an outcome studied. In some embodiments, “outcome” can refer to survival / mortality over a given time horizon. For example, “outcome” can refer to survival / mortality over 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or longer. In some embodiments, an increased risk for a poor outcome indicates that a therapy has had a poor efficacy, and a reduced risk for a poor outcome indicates that a therapy has had a good efficacy. As used herein, the term “high risk clinical trial” refers to one in which the test agent has “more than minimal risk” (as defined by the terminology used by institutional review boards, or IRBs). In some embodiments, a high risk clinical trial is a drug trial. As used herein, the term “low risk clinical trial” refers to one in which the test agent has “minimal risk” (as defined by the terminology used by IRBs). In some embodiments, a low risk clinical trial is one that is not a drug trial. In some embodiments, a low risk clinical trial is one DB1/ 147901903.2 58 that that involves the use of a monitor or clinical practice process. In some embodiments, a low risk clinical trial is an observational clinical trial. As used herein, the terms “modulated” or “modulation,” or “regulated” or “regulation” and “differentially regulated” can refer to both up regulation (i.e., activation or stimulation, e.g., by agonizing or potentiating) and down regulation (i.e., inhibition or suppression, e.g., by antagonizing, decreasing or inhibiting), unless otherwise specified or clear from the context of a specific usage. As used herein, the term “subject” refers to any suitable (e.g., treatable) member of the animal kingdom. In the methods, the subject is preferably a mammal. In the methods, the subject is preferably a human patient. In the methods, the subject may be a mammalian pediatric patient. In the methods, the pediatric patient is a mammalian (e.g., preferably human) patient under 18 years of age, while an adult patient is 18 or older. As used herein, the term “treating” (and its variations, such as “treatment” “treating,” “treat,” and the like) is, unless stated otherwise, to be considered in its broadest context and refers to obtaining a desired pharmacologic and/or physiologic effect. In particular, for example, the term “treating” may not necessarily imply or require that an animal is treated until total recovery. Accordingly, “treating” includes amelioration of the symptoms, relief from the symptoms or effects associated with a condition, decrease in severity of a condition, or preventing, preventively ameliorating symptoms, or otherwise reducing the risk of developing a particular condition. In some aspects, “treating” may not require or include prevention. As used herein, reference to “treating” an animal includes but is not limited to prophylactic treatment and therapeutic treatment. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or can be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease. “Treatment,” as used herein, covers any treatment of a disease in a subject, preferably in a mammal (e.g., in a human), and may include one or more of: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression or elimination of the disease and/or relieving one or more disease symptoms. In particular aspects of the methods, such as conditions or disorders characterized by dysregulated IRAK expression or dysregulated (e.g., hyperactive) IRAK-mediated signaling pathway(s), treatment may be or DB1/ 147901903.2 59 include reducing such expression or signaling. “Treatment” can also encompass delivery of an agent or administration of a therapy in order to provide for a pharmacologic effect, even in the absence of a disease or condition. Any of the compositions (e.g., pharmaceutical compositions) described herein can be used to treat a suitable subject. “Therapeutically effective amount” means an amount effective to achieve a desired and/or beneficial effect. An effective amount can be administered in one or more administrations. In the methods, a therapeutically effective amount is an amount appropriate to treat an indication. By treating an indication is meant achieving any desirable effect, such as one or more of palliate, ameliorate, stabilize, reverse, slow, or delay disease progression, increase the quality of life, or to prolong life. Such achievement can be measured by any suitable method, such as measurement of tumor size or blood cell count, or any other suitable measurement. As used herein, the term “marker” or “biomarker” refers to a biological molecule, such as, for example, a nucleic acid, peptide, protein, hormone, and the like, whose presence or concentration can be detected and correlated with a known condition, such as a disease state. It can also be used to refer to a differentially expressed gene whose expression pattern can be utilized as part of a predictive, prognostic or diagnostic process in healthy conditions or a disease state, or which, alternatively, can be used in methods for identifying a useful treatment or prevention therapy. As used herein, an mRNA “isoform” is an alternative transcript for a specific mRNA or gene. This term includes pre-mRNA, immature mRNA, mature mRNA, cleaved or otherwise truncated, shortened, or aberrant mRNA, modified mRNA (e.g. containing any residue modifications, capping variants, polyadenylation variants, etc.), and the like. “Antibody” or “antibody peptide(s)” refer to an intact antibody, or a binding fragment thereof that competes with the intact antibody for specific binding; this definition also encompasses monoclonal and polyclonal antibodies. Binding fragments are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab′, F(ab′)2, Fv, and single-chain antibodies. An antibody other than a “bispecific” or “bifunctional” antibody is understood to have each of its binding sites identical. An antibody, for example, substantially inhibits adhesion of a receptor to a counterreceptor when an excess of antibody reduces the quantity of receptor bound to DB1/ 147901903.2 60 counterreceptor by at least about 20%, 40%, 60% or 80%, and more usually greater than about 85% (as measured in an in vitro competitive binding assay). Embodiments of the disclosure set forth herein include disclosed compounds (e.g., Compound 8). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the disclosed compound. Still other embodiments of the disclosure include compositions (e.g., pharmaceutical compositions) for treating, for example, certain diseases using the disclosed compounds. Some embodiments include methods of using the disclosed compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating (e.g., diseases such as cancer or blood disorders). Some embodiments include methods of determining whether a patient is suitable for, or likely to respond favorably to, a particular treatment. Further embodiments include methods for making the disclosed compounds. Additional embodiments of the disclosure are also discussed herein. Compounds In one aspect, the present disclosure relates to or a salt, ester, solvate, optical isomer, geometric isomer, or
Figure imgf000062_0001
embodiment, the compounds disclosed herein (i.e., Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof) are an IRAK1, IRAK4, IRAK1/4, and/or FLT3 inhibitor. In one embodiment, the compounds disclosed herein are IRAK1/4, panFLT3 inhibitors. In one embodiment, Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of less than about 55 nM, less than about 50 nM, less than about 45 nM, less than about 40 nM, less than about 35 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of between about 27 nM and about 17 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, DB1/ 147901903.2 61 geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of about 30 nM, about 29 nM, about 28 nM, about 27 nM, about 25 nM, about 24 nM, about 23 nM, about 22 nM, about 21 nM, about 20 nM, about 19 nM, about 18 nM, about 17 nM, about 16 nM, or about 15 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of between about 5 nM and about 0.05 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of about 5 nM, about 4.5 nM, about 4 nM, about 3.5 nM, about 3 nM, about 2.5 nM, about 2 nM, about 1.5 nM, about 1 nM, or about 0.5 nM. In one embodiment, the compound has IRAK4:IRAK1 potency ratio of less than about 70, less than about 60, less than about 50, less than about 40, less than about 30, or less than about 20. In one embodiment, the IRAK4:IRAK1 potency ratio is calculated from the IRAK1 and IRAK4 IC50 measurements. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC50 of less than about 10 nM, less than about 8 nM, less than about 6 nM, less than about 4 nM, less than about 2 nM, or less than about 1 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC50 of between about 2 nM and about 0.01 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC50 of about 2.5 nM, about 2.25 nM, about 2 nM, about 1.75 nM, about 1.5 nM, about 1.25 nM, about 1 nM, about 0.75 nM, about 0.5 nM, about 0.25 nM, about 0.1 nM, or about 0.075 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, inhibits NF-kB-mediated signaling. In one embodiment, inhibition of IRAK1 and IRAK4 inhibits NF-kB-mediated signaling. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, inhibits TLR signaling and IL-1 signaling. In one embodiment, the inhibition of IRAK1 and IRAK4 inhibits TLR signaling and IL-1 signaling. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, inhibits IRAK1, IRAK4, and FLT3 DB1/ 147901903.2 62 Methods In one aspect, the present disclosure provides a method of treating an inflammatory disease/disorder, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS) in a subject in need thereof, the method comprising administering to the subject Compound 8:
Figure imgf000064_0001
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In one embodiment, the inflammatory disease/disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis. In one embodiment, the subject has or is suspected of having AML. In one embodiment, the AML is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML. In one embodiment, the AML is FLT3 wild type AML. In another embodiment, the AML is FLT3 mutant AML. In one embodiment, the subject has or is suspected of having MDS. In one embodiment, the MDS is MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2. In one embodiment, the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1, SRSF2, SF3B1, or ZRSR2. In one embodiment, the subject has FLT3 wild type AML. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, JAK2, ASXL1, ABL1, BCORL1, FBXW7, KDM6A, KRAS, SRSF2, TP53, CALR, ATRX, IDH1, IDH2, PDGFRA, SF3B1, GATA1, PTPN11, HRAS, MPL, PHF6, ATM, BCL11A, MLL3, TYK1, DB1/ 147901903.2 63 UTAF1, CTCF, CEBPA, ETV6, NOTCH1, STAG2, SETBP1, or WT1. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, KIT, or BCOR. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of TET2, KIT, and BCOR. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, BRAF, CDKN2A, or UTX. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of TET2, BRAF, CDKN2A, and UTX. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of ZRSR2, TET2, NPM1, PTEN, DNMT3A, or EZH2. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of ZRSR2, TET2, NPM1, PTEN, DNMT3A, and EZH2. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, RUNX1, JAK2, DNMT3A, or ASXL1. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of TET2, RUNX1, JAK2, DNMT3A, and ASXL1. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of ABL1, ASXL1, BCORL1, CBL, CDKN2A, FBXW7, KDM6A, KIT, KRAS, PTEN, SRSF2, TET2, or TP53. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of ABL1, ASXL1, BCORL1, CBL, CDKN2A, FBXW7, KDM6A, KIT, KRAS, PTEN, SRSF2, TET2, and TP53. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of ABL1, ASXL1, ATRX, BCOR, BCORL1, CALR, CDKN2A, DNMT3A, IDH1, KIT, KRAS, PDGFRA, PTEN, SF3B1, TET2, or TP53. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of ABL1, ASXL1, ATRX, BCOR, BCORL1, CALR, CDKN2A, DNMT3A, IDH1, KIT, KRAS, PDGFRA, PTEN, SF3B1, TET2, and TP53. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of ASXL1, BCORL1, BRAF, CDKN2A, DNMT3A, EZH2, HRAS, KIT, KRAS, MPL, PHF6, PTEN, RUNX1, TET2, TP53, or WT1. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of ASXL1, BCORL1, BRAF, CDKN2A, DNMT3A, EZH2, HRAS, KIT, KRAS, MPL, PHF6, PTEN, RUNX1, TET2, TP53, and WT1. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of ABL1, ASXL1, ATRX, BCORL1, CBL, CDKN2A, DNMT3A, GATA1, JAK2, KDM6A, KIT, KRAS, PTEN, PTPN11, SRSF2, TET2, or TP53. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of ABL1, ASXL1, ATRX, BCORL1, CBL, CDKN2A, DNMT3A, GATA1, JAK2, KDM6A, KIT, KRAS, DB1/ 147901903.2 64 PTEN, PTPN11, SRSF2, TET2, and TP53. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of BCL11A, RUNX1, ATM, DNMT3A, CTCF, KIT, U2AF1, IDH1, TYK2, or MLL3. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of BCL11A, RUNX1, ATM, DNMT3A, CTCF, KIT, U2AF1, IDH1, TYK2, and MLL3. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of ABL1, ASXL1, BCORL1, BRAF, CDKN2A, CEBPA, DNMT3A, ETV6, EZH2, IDH2, KDM6A, KIT, KRAS, PTEN, RUNX1, SF3B1, TET2, TP53, or ZRSR2. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of ABL1, ASXL1, BCORL1, BRAF, CDKN2A, CEBPA, DNMT3A, ETV6, EZH2, IDH2, KDM6A, KIT, KRAS, PTEN, RUNX1, SF3B1, TET2, TP53, and ZRSR2. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of ASXL1, ATRX, BCORL1, BRAF, DNMT3A, EZH2, FBXW7, GATA1, KDM6A, KIT, KRAS, NOTCH1, PTEN, RUNX1, STAG2, TET2, or TP53. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of ASXL1, ATRX, BCORL1, BRAF, DNMT3A, EZH2, FBXW7, GATA1, KDM6A, KIT, KRAS, NOTCH1, PTEN, RUNX1, STAG2, TET2, and TP53. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of ABL1, ASXL1, BCORL1, CDKN2A, CEBPA, HRAS, IDH1, KDM6A, KRAS, NOTCH1, PTEN, SRSF2, or TP53. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of ABL1, ASXL1, BCORL1, CDKN2A, CEBPA, HRAS, IDH1, KDM6A, KRAS, NOTCH1, PTEN, SRSF2, and TP53. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of ATRX, BCOR, BCORL1, BRAF, CDKN2A, FBXW7, KIT, NRAS, PTEN, RUNX1, STAG2, TET2, or TP53. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of ATRX, BCOR, BCORL1, BRAF, CDKN2A, FBXW7, KIT, NRAS, PTEN, RUNX1, STAG2, TET2, and TP53. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of ABL1, ASXL1, BCOR, BCORL1, BRAF, CDKN2A, ETV6, FBXW7, KDM6A, KRAS, PTEN, PTPN11, RUNX1, SETBP1, SRSF2, TET2, TP53, or WT1. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of ABL1, ASXL1, BCOR, BCORL1, BRAF, CDKN2A, ETV6, FBXW7, KDM6A, KRAS, PTEN, PTPN11, RUNX1, SETBP1, SRSF2, TET2, TP53, and WT1. In one embodiment, Compound 8, or a salt, ester, solvate, optical DB1/ 147901903.2 65 isomer, geometric isomer, or salt of an isomer thereof treats FLT3 wild type AML regardless of the additional AML mutational status of the subject. In one embodiment, the subject has FLT3 mutant AML with a FLT3-ITD mutation and a gene mutation in one or more of TET2, DNMT3A, or NPM1. In one embodiment, the subject has FLT3 mutant AML with a FLT3-ITD mutation and a gene mutation in each of TET2, DNMT3A, and NPM1. In one embodiment, the subject has FLT3 mutant AML with a FLT3- ITD mutation and/or a FLT3(D835Y) mutation. In one embodiment, the subject has FLT3 mutant AML with each of a FLT3-ITD mutation and a FLT3(D835Y) mutation. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ABL1, ATRX, BCORL1, BRAF, CDKN2A, DNMT3A, KDM6A, KRAS, PTEN, PTPN11, RUNX1, TET2, or TP53. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ABL1, ATRX, BCORL1, BRAF, CDKN2A, DNMT3A, KDM6A, KRAS, PTEN, PTPN11, RUNX1, TET2, and TP53. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ASXL1, BCORL1, CDKN2A, CEBPA, DNMT3A, FBXW7, HRAS, IDH1, JAK2, KIT, NPM1, NRAS, PDGFRA, PTEN, PTPN11, SF3B1, TET2, or TP53. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ASXL1, BCORL1, CDKN2A, CEBPA, DNMT3A, FBXW7, HRAS, IDH1, JAK2, KIT, NPM1, NRAS, PDGFRA, PTEN, PTPN11, SF3B1, TET2, and TP53. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ASXL1, BCORL1, BRAF, CBL, DNMT3A, ETV6, JAK2, KIT, PDGFRA, PHF6, PTEN, PTPN11, RUNX1, TET2, or TP53. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ASXL1, BCORL1, BRAF, CBL, DNMT3A, ETV6, JAK2, KIT, PDGFRA, PHF6, PTEN, PTPN11, RUNX1, TET2, and TP53. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ABL1, ASXL1, ATRX, BCORL1, CDKN2A, CEBPA, FBXW7, GATA1, KRAS, NOTCH1, PTEN, TET2, TP53, or WT1. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ABL1, ASXL1, ATRX, BCORL1, CDKN2A, CEBPA, FBXW7, GATA1, KRAS, NOTCH1, PTEN, TET2, TP53, and WT1. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ABL1, ASXL1, ATRX, BCORL1, CDKN2A,DNMT3A, ETV6, KDM6A, KIT, KRAS, NOTCH1, NRAS, PDGFRA, PTEN, PTPN11, RUNX1, SETBP1, TET2, DB1/ 147901903.2 66 or TP53. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ABL1, ASXL1, ATRX, BCORL1, CDKN2A,DNMT3A, ETV6, KDM6A, KIT, KRAS, NOTCH1, NRAS, PDGFRA, PTEN, PTPN11, RUNX1, SETBP1, TET2, and TP53. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ABL1, ASXL1, ATRX, BCORL1, BRAF, CBL, CDKN2A, ETV6, GNAS, HRAS, JAK2, KDM6A, PTEN, TET2, or TP53. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ABL1, ASXL1, ATRX, BCORL1, BRAF, CBL, CDKN2A, ETV6, GNAS, HRAS, JAK2, KDM6A, PTEN, TET2, and TP53. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in one or more of ABL1, ASXL1, BCORL1, BRAF, CBL, CDKN2A, FBX, HRAS, IDH2, KDM6A, KIT, PTEN, RAD21, RUI, TET2, or TP53. In one embodiment, the subject has FLT3 mutant AML with a gene mutation in FLT3 and in each of ABL1, ASXL1, BCORL1, BRAF, CBL, CDKN2A, FBX, HRAS, IDH2, KDM6A, KIT, PTEN, RAD21, RUI, TET2, and TP53. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats FLT3 mutant AML regardless of the additional AML mutational status of the subject. In one embodiment, the subject has MDS with a gene mutation in U2AF1. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats MDS regardless of the MDS mutational status of the subject. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of less than about 55 nM, less than about 50 nM, less than about 45 nM, less than about 40 nM, less than about 35 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of between about 27 nM and about 17 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of about 30 nM, about 29 nM, about 28 nM, about 27 nM, about 25 nM, about 24 nM, about 23 nM, about 22 nM, about 21 nM, about 20 nM, about 19 nM, about 18 nM, about 17 nM, about 16 nM, or about 15 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of less than about 30 nM, less than about 25 nM, less DB1/ 147901903.2 67 than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of between about 5 nM and about 0.05 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of about 5 nM, about 4.5 nM, about 4 nM, about 3.5 nM, about 3 nM, about 2.5 nM, about 2 nM, about 1.5 nM, about 1 nM, or about 0.5 nM. In one embodiment, the compound has IRAK4:IRAK1 potency ratio of less than about 70, less than about 60, less than about 50, less than about 40, less than about 30, or less than about 20. In one embodiment, the IRAK4:IRAK1 potency ratio is calculated from the IRAK1 and IRAK4 IC50 measurements. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC50 of less than about 10 nM, less than about 8 nM, less than about 6 nM, less than about 4 nM, less than about 2 nM, or less than about 1 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC50 of between about 2 nM and about 0.01 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC50 of about 2.5 nM, about 2.25 nM, about 2 nM, about 1.75 nM, about 1.5 nM, about 1.25 nM, about 1 nM, about 0.75 nM, about 0.5 nM, about 0.25 nM, about 0.1 nM, or about 0.075 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, inhibits NF-kB-mediated signaling. In one embodiment, inhibition of IRAK1 and IRAK4 inhibits NF-kB-mediated signaling. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits TLR signaling and IL-1 signaling. In one embodiment, the inhibition of IRAK1 and IRAK4 inhibits TLR signaling and IL-1 signaling. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, inhibits IRAK1, IRAK4, and FLT3. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits FLT3. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, treats AML and/or MDS in the subject by suppressing leukemic stem/progenitor cell (LSPC) function and inducing differentiation. In one embodiment, the inhibition of IRAK1 and DB1/ 147901903.2 68 IRAK4 by the compound of the disclosure promotes the suppression of LSPC function and the induction of differentiation in the subject with AML and/or MDS. In one embodiment, the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes and/or decreased expression of one or more IRAK1/4-associated genes. In one embodiment, the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes compared to a healthy control subject and/or decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject. In one embodiment, the subject in need thereof has elevated expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes. In one embodiment, the subject in need thereof has elevated expression of one or more IRAK1/4- associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. In one embodiment, the subject in need thereof has elevated expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. In one embodiment, the subject in need thereof has decreased expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes compared to a DB1/ 147901903.2 69 healthy control subject. In one embodiment, the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. In one embodiment, the subject in need thereof has decreased expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. In one embodiment, the subject in need thereof has increased secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines. In one embodiment, the subject in need thereof has increased secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ. In one embodiment, the subject in need thereof has increased secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines compared to a healthy control subject. In one embodiment, the subject in need thereof has increased secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ compared to the healthy control subject. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject and/or increases the expression of one of more DB1/ 147901903.2 70 IRAK1/4-associated genes found to be decreased in the subject. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8 and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, DB1/ 147901903.2 71 PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an DB1/ 147901903.2 72 isomer thereof decreases the secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered to the subject in need thereof via parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered to the subject in need thereof in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight. In one embodiment, a composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered to the subject in need thereof. In one embodiment, the composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof further comprises one or more pharmaceutically acceptable carriers, excipients, or additives. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject. In one embodiment, the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, continues to treat the inflammatory disease/disorder, AML, or MDS in the subject after the administration is stopped. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, DB1/ 147901903.2 73 about one week, about two weeks, about three weeks, or about a month after the administration is stopped. In one embodiment, the method further comprises administering Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, in combination with one or more additional agents selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody- drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered to the subject in need thereof in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a gluococorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. In one embodiment, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof. In one embodiment, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof. In one embodiment, the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor. In one embodiment, the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a DB1/ 147901903.2 74 pharmaceutically acceptable salt of any one thereof. In one embodiment, the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, one or more compositions comprising the one or more additional agents are administered to the subject in need thereof. In one embodiment, the one or more compositions comprising the one or more additional agents further comprise a pharmaceutically acceptable carrier, excipient, or additive. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered sequentially with the one or more additional agents. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered concurrently with the one or more additional agents. In one embodiment, the composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered sequentially with the composition comprising the one or more additional agents. one embodiment, the composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered concurrently with the composition comprising the one or more additional agents. In another aspect, the present disclosure provides a method of determining a subject with a disease/disorder that can be treated by the administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, the method comprising: determining that a subject with an inflammatory disease/disorder, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS) has elevated expression of one or more IRAK1/4- associated genes and/or decreased expression of one or more IRAK1/4-associated genes; and administering to the subject Compound 8:
Figure imgf000076_0001
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, thus treating the inflammatory disease/disorder, AML, or MDS. In one embodiment, the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes and/or decreased DB1/ 147901903.2 75 expression of one or more IRAK1/4-associated genes compared to a healthy control subject. In one embodiment, the inflammatory disease/disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis. In one embodiment, the subject has or is suspected of having AML. In one embodiment, the AML is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML. In one embodiment, the AML is FLT3 wild type AML. In another embodiment, the AML is FLT3 mutant AML. In one embodiment, the subject has or is suspected of having MDS. In one embodiment, the MDS is MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2. In one embodiment, the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1, SRSF2, SF3B1, or ZRSR2. In one embodiment, the subject has FLT3 wild type AML. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, JAK2, or ASXL1. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, KIT, or BCOR. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of TET2, KIT, and BCOR. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, BRAF, CDKN2A, or UTX. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of TET2, BRAF, CDKN2A, and UTX. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of ZRSR2, TET2, NPM1, PTEN, DNMT3A, or EZH2. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of ZRSR2, TET2, NPM1, PTEN, DNMT3A, and EZH2. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in one or more of TET2, RUNX1, JAK2, DNMT3A, or ASXL1. In one embodiment, the subject has FLT3 wild type AML with a gene mutation in each of TET2, RUNX1, JAK2, DNMT3A, and ASXL1. In one embodiment, Compound 8, or a salt, ester, DB1/ 147901903.2 76 solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats FLT3 wild type AML regardless of the additional AML mutational status of the subject. In one embodiment, the subject has FLT3 mutant AML with a FLT3-ITD mutation and a gene mutation in one or more of TET2, DNMT3A, or NPM1. In one embodiment, the subject has FLT3 mutant AML with a FLT3-ITD mutation and a gene mutation in each of TET2, DNMT3A, and NPM1. In one embodiment, the subject has FLT3 mutant AML with a FLT3- ITD mutation and/or a FLT3(D835Y) mutation. In one embodiment, the subject has FLT3 mutant AML with each of a FLT3-ITD mutation and a FLT3(D835Y) mutation. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats FLT3 mutant AML regardless of the additional AML mutational status of the subject. In one embodiment, the subject has MDS with a gene mutation in U2AF1. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats MDS regardless of the MDS mutational status of the subject. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of less than about 55 nM, less than about 50 nM, less than about 45 nM, less than about 40 nM, less than about 35 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of between about 27 nM and about 17 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of about 30 nM, about 29 nM, about 28 nM, about 27 nM, about 25 nM, about 24 nM, about 23 nM, about 22 nM, about 21 nM, about 20 nM, about 19 nM, about 18 nM, about 17 nM, about 16 nM, or about 15 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of between about 5 nM and about 0.05 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of about 5 nM, about 4.5 nM, about 4 nM, about 3.5 nM, DB1/ 147901903.2 77 about 3 nM, about 2.5 nM, about 2 nM, about 1.5 nM, about 1 nM, or about 0.5 nM. In one embodiment, the compound has IRAK4:IRAK1 potency ratio of less than about 70, less than about 60, less than about 50, less than about 40, less than about 30, or less than about 20. In one embodiment, the IRAK4:IRAK1 potency ratio is calculated from the IRAK1 and IRAK4 IC50 measurements. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC50 of less than about 10 nM, less than about 8 nM, less than about 6 nM, less than about 4 nM, less than about 2 nM, or less than about 1 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC50 of between about 2 nM and about 0.01 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has a FLT3 IC50 of about 2.5 nM, about 2.25 nM, about 2 nM, about 1.75 nM, about 1.5 nM, about 1.25 nM, about 1 nM, about 0.75 nM, about 0.5 nM, about 0.25 nM, about 0.1 nM, or about 0.075 nM. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, inhibits NF-kB-mediated signaling. In one embodiment, inhibition of IRAK1 and IRAK4 inhibits NF-kB-mediated signaling. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits TLR signaling and IL-1 signaling. In one embodiment, the inhibition of IRAK1 and IRAK4 inhibits TLR signaling and IL-1 signaling. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, inhibits IRAK1, IRAK4, and FLT3. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof inhibits FLT3. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, treats AML and/or MDS in the subject by suppressing leukemic stem/progenitor cell (LSPC) function and inducing differentiation. In one embodiment, the inhibition of IRAK1 and IRAK4 by the compound of the disclosure promotes the suppression of LSPC function and the induction of differentiation in the subject with AML and/or MDS. In one embodiment, the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes and/or decreased expression of one or more IRAK1/4-associated genes. In one embodiment, the subject in need thereof has elevated expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, DB1/ 147901903.2 78 seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes. In one embodiment, the subject in need thereof has elevated expression of one or more IRAK1/4- associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. In one embodiment, the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes compared to a healthy control subject and/or decreased expression of one or more IRAK1/4- associated genes compared to a healthy control subject. In one embodiment, the subject in need thereof has elevated expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes compared to a healthy control subject. In one embodiment, the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 compared to the healthy control subject. In one embodiment, the subject in need thereof has elevated expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, DB1/ 147901903.2 79 CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 compared to the healthy control subject. In one embodiment, the subject in need thereof has decreased expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes. In one embodiment, the subject in need thereof has decreased expression of one or more IRAK1/4- associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. In one embodiment, the subject in need thereof has decreased expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. In one embodiment, the subject in need thereof has decreased expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes compared to a healthy control subject. In one embodiment, the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, DB1/ 147901903.2 80 SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 compared to the healthy control subject. In one embodiment, the subject in need thereof has decreased expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 compared to the healthy control subject. In one embodiment, the subject in need thereof has elevated secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines. In one embodiment, the subject in need thereof has elevated secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ. In one embodiment, the subject in need thereof has elevated secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines compared to a healthy control subject. In one embodiment, the subject in need thereof has elevated secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ compared to the healthy control subject. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8 and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the DB1/ 147901903.2 81 expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes DB1/ 147901903.2 82 in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, DB1/ 147901903.2 83 VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines in the subject in need thereof. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the secretion of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered to the subject in need thereof via parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered to the subject in need thereof in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered to the subject in a dosage of from about 1 µM to about 10,000 µM, about 1 µM to about 950 µM, about 1 µM to about 900 µM, about 1 µM to about 850 µM, about 1 µM to about 700 µM, about 1 µM to about 650 µM, about 1 µM to about 600 µM, about 1 µM to about 550 µM, DB1/ 147901903.2 84 about 1 µM to about 500 µM, about 1 µM to about 450 µM, about 1 µM to about 400 µM, about 1 µM to about 350 µM, about 1 µM to about 300 µM, about 1 µM to about 250 µM, about 1 µM to about 200 µM, about 1 µM to about 150 µM, about 1 µM to about 100 µM, or about 1 µM to about 50 µM. In one embodiment, a composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered to the subject in need thereof. In one embodiment, the composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof further comprises one or more pharmaceutically acceptable carriers, excipients, or additives. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject. In one embodiment, the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, treats the inflammatory disease/disorder, AML, or MDS in the subject while the compound is administered to the subject. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, continues to treat the inflammatory disease/disorder, AML, or MDS in the subject after the administration is stopped. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped. In one embodiment, the method further comprises administering Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, in combination with one or more additional agents selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue DB1/ 147901903.2 85 (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody- drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered to the subject in need thereof in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a gluococorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. In one embodiment, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof. In one embodiment, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof. In one embodiment, the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor. In one embodiment, the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof. In one embodiment, the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, one or more compositions comprising the one or more additional agents are administered to the subject in need thereof. In one embodiment, the one or more compositions comprising the one or more additional agents further comprise a pharmaceutically acceptable carrier, excipient, or additive. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered DB1/ 147901903.2 86 sequentially with the one or more additional agents. In one embodiment, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered concurrently with the one or more additional agents. In one embodiment, the composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered sequentially with the composition comprising the one or more additional agents. one embodiment, the composition comprising Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered concurrently with the composition comprising the one or more additional agents. Clauses of the disclosure Clause 1. A method of treating an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in a subject in need thereof, the method comprising administering to the subject a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 1a. The method of clause 1, wherein the compound is Compound 8:
Figure imgf000088_0001
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 2. The method of clause 1 or 1a, wherein the inflammatory disease or disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, and colitis. Clause 3. The method of clause 1 or 1a, wherein the acute myeloid leukemia (AML) is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating DB1/ 147901903.2 87 agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML. Clause 4. The method of any one of clauses 1, 1a, or 3, wherein the subject has acute myeloid leukemia (AML) and the subject has a gene mutation in one or more of FLT3, TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, JAK2, ASXL1, ABL1, ATRX, BCORL1, KDM6A, PTPN11, TP53, CBL, CEBPA, FBXW7, HRAS, NRAS, IDH1, IDH2, NRAS, PDGFRA, SF3B1, ETV6, PHF6, GNAS, KRAS, NOTCH1, STAG2, SETBP1, GATA1, GATA2, WT1, SRSF2, GNAS, CEBPA, CALR, MPL, BCL11A, ATM, CTCF, U2AF1, TYK2, FBX, RUI, RAD21, or MLL3. Clause 5. The method of clause 1 or 1a, wherein the myelodysplastic syndrome (MDS) is MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2. Clause 6. The method of any one of clauses 1, 1a, or 5, wherein the subject has myelodysplastic syndrome (MDS) and the subject has a gene mutation in one or more of U2AF1, FLT3, ASXL1, BCORL1, BRAF, CBL, CDKN2A, DNMT3A, FBXW7, GATA2, IDH2, KRAS, NOTCH1, NRAS, PDGFRA, PTEN, PTPN11, TET2, TP53, EZH2, HRAS, KIT, MPL, PHF6, RUNX1, WT1, ABL1, CEBPA, ETV6, IDH2, KDM6A, KIT, KRAS, PTEN, RUNX1, SF3B1, ZRSR2. Clause 7. The method of clause 5, wherein the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1, SRSF2, SF3B1, or ZRSR2. Clause 8. The method of any one of clauses 1 to 7, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has an IRAK1 IC50 of less than about 40 nM. Clause 8a. The method of any one of clauses 1 to 7, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of less than about 40 nM. Clause 9. The method of any one of clauses 1 to 8a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, DB1/ 147901903.2 88 CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has an IRAK4 IC50 of less than about 5 nM. Clause 9a. The method of any one of clauses 1 to 9, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of less than about 5 nM. Clause 10. The method of any one of clauses 1 to 9a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has IRAK4:IRAK1 potency ratio of less than about 40. Clause 10a. The method of any one of clauses 1 to 10, wherein Compound 8, Compound 9, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has IRAK4:IRAK1 potency ratio of less than about 40. Clause 11. The method of any one of clauses 1 to 10a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has an FLT3 IC50 of less than about 2.5 nM. Clause 11a. The method of any one of clauses 1 to 11, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an FLT3 IC50 of less than about 2.5 nM. Clause 12. The method of any one of clauses 1 to 11, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes and/or decreased expression of one or more IRAK1/4-associated genes. Clause 12a. The method of clause 12, wherein the subject in need thereof has elevated expression and/or decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject. Clause 13. The method of clause 12 or 12a, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, DB1/ 147901903.2 89 CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4 PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, DB1/ 147901903.2 90 CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7 IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 14. The method of any one of clauses 12, 12a, or 13, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, DB1/ 147901903.2 91 SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. Clause 15. The method of clause 12 or 12a, wherein the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, DB1/ 147901903.2 92 NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, DB1/ 147901903.2 93 ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 16. The method of any one of clauses 12, 12a, or 15, wherein the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. Clause 17. The method of any one of clauses 1 to 16, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more IRAK1/4- associated genes in the subject and/or increases the expression of one of more IRAK1/4- associated genes in the subject. Clause 17a. The method of any one of clauses 1 to 16, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject. Clause 17b. The method of any one of clauses 1 to 17, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject. Clause 17c. The method of any one of clauses 17 to 17b, wherein the administration of DB1/ 147901903.2 94 Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of the one or more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and/or increases the expression of the one or more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA- 4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 17d. The method of any one of clauses 17, 17a, 17b, or 17c, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of the one or more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and/or increases the expression of the one or more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 17e. The method of any one of clauses 17 to 17d, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA- 4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 17f. The method of any one of clauses 17 to 17e, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric DB1/ 147901903.2 95 isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 18. The method of any one of clauses 17 to 17f, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, DB1/ 147901903.2 96 VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, DB1/ 147901903.2 97 THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7 IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 18a. The method of any one of clauses 17 to 18, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, DB1/ 147901903.2 98 H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, DB1/ 147901903.2 99 SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7 IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 19. The method of any one of clauses 17 to 17f, 18, or 18a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 19a. The method of any one of clauses 17 to 17e, 18, 18a, or 19, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 20. The method of any one of clauses 17 to 17f, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound DB1/ 147901903.2 100 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof increases the expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, DB1/ 147901903.2 101 AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7 DB1/ 147901903.2 102 IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 20a. The method of any one of clauses 17 to 17f or 20, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof increases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, DB1/ 147901903.2 103 KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, DB1/ 147901903.2 104 FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7 IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 21. The method of any one of clauses 17 to 17f, 20, or 20a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 21a. The method of any one of clauses 17 to 17f, 20, 20a, or 21 wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 22. The method of any one of clauses 1 to 21a, wherein the subject in need thereof has elevated expression of one or more NFκB-associated genes and/or decreased expression of one or more NFκB-associated genes. Clause 22a. The method of clause 22, wherein the subject in need thereof has elevated expression of one or more NFκB-associated genes compared to a healthy control subject, and/or decreased expression of one or more NFκB-associated genes compared to a healthy control subject. DB1/ 147901903.2 105 Clause 23. The method of clause 22 or 22a, wherein the subject in need thereof has elevated expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, DB1/ 147901903.2 106 PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 24. The method of clause 22 or 22a, wherein the subject in need thereof has decreased expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, DB1/ 147901903.2 107 HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 25. The method of any one of clauses 1 to 24, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more NFκB-associated genes found to be elevated in the subject and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject. Clause 25a. The method of any one of clauses 1 to 25, wherein the administration of DB1/ 147901903.2 108 Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one of more NFκB-associated genes found to be elevated in the subject and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject. Clause 25b. The method of clause 25 or 25a, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of the one or more NFκB-associated genes found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of the one or more NFκB-associated genes found to be decreased in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 25c. The method of any one of clauses 25, 25a, or 25b, wherein the administration of Compound 8 decreases the expression of the one or more NFκB-associated genes found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and/or increases the expression of the one or more NFκB-associated genes found to be decreased in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 25d. The method of any one of clauses 25 to 25c, wherein upon administration to the subject, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one or more NFκB-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more NFκB-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 25e. The method of any one of clauses 25 to 25d, wherein upon administration to the subject, Compound 8, or a salt, ester, solvate, optical isomer, DB1/ 147901903.2 109 geometric isomer, or salt of an isomer thereof, decreases the expression of one or more NFκB- associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more NFκB-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 25f. The method of any one of clauses 1 to 24, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more NFκB-associated genes in the subject and/or increases the expression of one of more NFκB-associated genes in the subject. Clause 26. The method of any one of clauses 25 to 25f, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, DB1/ 147901903.2 110 GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 26a. The method of any one of clauses 25 to 26, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, DB1/ 147901903.2 111 BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, DB1/ 147901903.2 112 TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 27. The method of any one of clauses 25 to 25f, 26, or 26a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, DB1/ 147901903.2 113 IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 27a. The method of any one of clauses 25 to 25f, 26, 26a, or 27 wherein Compound 8, Compound 9, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, DB1/ 147901903.2 114 CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, DB1/ 147901903.2 115 TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 27b. The method of any one of clauses 1 to 27a, wherein the subject in need thereof has elevated secretion of one or more cytokines, optionally wherein the one or more cytokines are selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM- CSF, and IFN-γ. Clause 27c. The method of clause 27b, wherein the subject in need thereof has elevated secretion of one or more cytokines compared to a healthy control subject, optionally wherein the one or more cytokines are selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL- 10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ. Clause 27d. The method of any one of clauses 27a to 27c, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the secretion of one or more cytokines found to be elevated in the subject, optionally wherein the compound decreases the secretion of one or more cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ in the subject. Clause 27e. The method of any one of clauses 27a to 27e, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the secretion of one or more cytokines found to be elevated in the subject, optionally wherein the compound decreases the secretion of one or more cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ in the subject. Clause 27f. The method of clause 27e, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of the one or more cytokines found to be elevated in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one DB1/ 147901903.2 116 thereof, and/or increases the expression of the one or more cytokines found to be decreased in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 27g. The method of clause 27e or 27f, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of the one or more cytokines found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and/or increases the expression of the one or more cytokines found to be decreased in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 27h. The method of any one of clauses 27e to 27g, wherein upon administration to the subject, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one or more cytokines found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more cytokines found to be decreased in the subject compared to a healthy control subject. Clause 27i. The method of any one of clauses 27e to 27h, wherein upon administration to the subject, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more cytokines found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more cytokines found to be decreased in the subject compared to a healthy control subject. Clause 27j. The method of any one of clauses 27 to 27i, wherein upon administration to the subject, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more cytokines in the subject, and/or DB1/ 147901903.2 117 increases the expression of one or more cytokines in the subject compared to a healthy control subject. Clause 28. The method of any one of clauses 1 to 27j, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. Clause 28a. The method of any one of clauses 1 to 27i or 28, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. Clause 29. The method of any one of clauses 1 to 28a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject. Clause 29a. The method of any one of clauses 1 to 29, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject. Clause 30. The method of clause 29 or 29a, wherein the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. Clause 31. The method of any one of clauses 1 to 30, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, continues to treat the inflammatory disease/disorder, AML, or MDS in the subject after the administration is stopped. Clause 31a. The method of any DB1/ 147901903.2 118 one of clauses 1 to 31, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, continues to treat the inflammatory disease/disorder, AML, or MDS in the subject after the administration is stopped. Clause 32. The method of clause 31 or 31a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped. Clause 32a. The method of clause 31, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped. Clause 33. The method of any one of clauses 1 to 32a, wherein the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. Clause 34. The method of any one of clauses 1 to 33, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight or in a dosage of from about 0.35 mg to about 70,000 mg. Clause 34a. The method of any one of clauses 1 to 34, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight or in a dosage of from about 0.35 mg to about 70,000 mg. DB1/ 147901903.2 119 Clause 35. The method of any one of clauses 1 to 34a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. Clause 35a. The method of any one of clauses 1 to 35, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody- drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a DB1/ 147901903.2 120 steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. Clause 36. The method of clause 35 or 35a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. Clause 36a. The method of any one of clauses 35, 35a, or 36 wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. Clause 37. The method of any one of clauses 35, 35a, 36, or 36a, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. Clause 38. The method of clause 37, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject. Clause 38a. The method of clause 37 or 38, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject. DB1/ 147901903.2 121 Clause 39. The method of clause 38 or 38a, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 39a. The method of any one of clauses 38, 38a, or 39, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 40. The method of clause 39 or 39a, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 40a. The method of any one of clauses 39, 39a, or 40, wherein the combination of Compound 8, or a salt, ester, DB1/ 147901903.2 122 solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 41. The method of any one of clauses 38 to 40a, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by treating AML in the subject. Clause 41a. The method of any one of clauses 38 to 41, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by treating AML in the subject. Clause 42. The method of any one of clauses 35, 35a, 36, or 36a, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof or acalabrutinib or a pharmaceutically acceptable salt thereof. Clause 43. The method of any one of clauses 35, 35a, 36, or 36a, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof. Clause 44. The method of any one of clauses 35, 35a, 36, or 36a, wherein the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor. Clause 45. The method of clause 44, wherein the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof. Clause 46. The method of any one of clauses 35, 35a, 36, or 36a, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. Clause 47. A method of determining whether a subject with a an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic DB1/ 147901903.2 123 syndrome (MDS) can be treated by the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA- 4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, the method comprising: determining whether the subject has elevated expression of one or more IRAK1/4- associated genes and/or decreased expression of one or more IRAK1/4-associated genes, wherein the IRAK1/4-associated genes are selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, DB1/ 147901903.2 124 SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, DB1/ 147901903.2 125 YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 48. The method of clause 47, wherein the IRAK1/4-associated genes are selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. Clause 48a. The method of clause 47 or 48, wherein the method comprises determining whether a subject with an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be treated by the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 49. The method of any one of clauses 47, 48, or 48a, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes compared to a healthy control subject and/or decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject. Clause 50. The method of any one of clauses 47 to 49, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, DB1/ 147901903.2 126 CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, DB1/ 147901903.2 127 JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 51. The method of any one of clauses 47 to 50, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. DB1/ 147901903.2 128 Clause 52. The method of any one of clauses 47, 48, or 49, wherein the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, DB1/ 147901903.2 129 ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, DB1/ 147901903.2 130 LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 53. The method of any one of clauses 47, 48, 49, or 52, wherein the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. Clause 54. The method of any one of clauses 47 to 53, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one of more IRAK1/4- associated genes found to be elevated in the subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject. Clause 54a. The method of any one of clauses 47 to 54, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject. Clause 54b. The method of clause 54 or 54a, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of the one or more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of the one or more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound DB1/ 147901903.2 131 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 54c. The method of any one of clauses 54 to 54b, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of the one or more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and/or increases the expression of the one or more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 54d. The method of any one of clauses 54 to 54c, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more IRAK1/4- associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 54e. The method of any one of clauses 54 to 54d, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more IRAK1/4- associated genes found to be decreased in the subject compared to a healthy control subject. Clause 55. The method of any one of clauses 54 to 54e, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, DB1/ 147901903.2 132 PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DB1/ 147901903.2 133 DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject. Clause 55a. The method of any one of clauses 54 to 54e or 55, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, DB1/ 147901903.2 134 CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, DB1/ 147901903.2 135 CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject. Clause 56. The method of any one of clauses 54 to 54e, 55, or 55a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound DB1/ 147901903.2 136 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 56a. The method of any one of clauses 54 to 54e, 55, 55a, or 56, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 57. The method of any one of clauses 54 to 54e, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, DB1/ 147901903.2 137 TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, DB1/ 147901903.2 138 KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject. Clause 57a. The method of any one of clauses 54 to 54e or 57, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, DB1/ 147901903.2 139 SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, DB1/ 147901903.2 140 HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject. Clause 58. The method of any one of clauses 54 to 54e, 57, or 57a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, DB1/ 147901903.2 141 ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 58a. The method of any one of clauses 54, 54a, 54b, 57, or 58, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 59. A method of determining whether a subject with an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be treated by the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, the method comprising: determining whether the subject has elevated expression of one or more NFκB-associated genes and/or decreased expression of one or more NFκB-associated genes, wherein the NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, DB1/ 147901903.2 142 CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, DB1/ 147901903.2 143 TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 59a. The method of clause 59, wherein the method comprising determining whether a subject with an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be treated by the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 60. The method of clause 59 or 59a, wherein the subject in need thereof has elevated expression of one or more NFκB-associated genes compared to a healthy control subject and/or decreased expression of one or more NFκB-associated genes compared to a healthy control subject. Clause 61. The method of any one of clauses 59, 59a, or 60, wherein the subject in need thereof has elevated expression of one or more NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, DB1/ 147901903.2 144 IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 62. The method of any one of clauses 59, 59a, 60, or 61, wherein the subject in need thereof has decreased expression of one or more NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, DB1/ 147901903.2 145 CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, DB1/ 147901903.2 146 TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 63. The method of any one of clauses 59 to 62, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one of more NFκB-associated genes found to be elevated in the subject and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject. Clause 63a. The method of any one of clauses 59 to 63, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one of more NFκB-associated genes found to be elevated in the subject and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject. Clause 63b. The method of clause 63 or 63a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one or more NFκB-associated genes found to be elevated in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and/or increases the expression of one or more NFκB- associated genes found to be decreased in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. DB1/ 147901903.2 147 Clause 63c. The method of any one of clauses 63 to 63b, wherein Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more NFκB-associated genes found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and/or increases the expression of one or more NFκB-associated genes found to be decreased in the subject before the administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 63d. The method of any one of clauses 63 to 63c, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one or more NFκB-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more NFκB-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 63e. The method of any one of clauses 63 to 63d, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more NFκB-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more NFκB-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 64. The method of any one of clauses 63 to 63e, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one or more NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, DB1/ 147901903.2 148 CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, DB1/ 147901903.2 149 TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. Clause 64a. The method of any one of clauses 63 to 63e or 64, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one or more NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, DB1/ 147901903.2 150 NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. Clause 65. The method of any one of clauses 63 to 63e, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one or more NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, DB1/ 147901903.2 151 CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. DB1/ 147901903.2 152 Clause 65a. The method of any one of clauses 63 to 63e or 65, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one or more NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, DB1/ 147901903.2 153 POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. Clause 65b. A method of determining whether a subject with an inflammatory disease or disorder, or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), can be treated by the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA- 4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, the method comprising: determining whether the subject has an elevated secretion of one or more cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM- CSF, and IFN-γ. Clause 65c. The method of clause 65b, wherein the method comprises determining whether a subject with an inflammatory disease or disorder, or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), can be treated by the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 65d. The method of clause 65b or 65c, wherein the subject has elevated expression of one or more cytokines compared to a healthy control subject and/or a decreased expression of one or more cytokines compared to a healthy control subject. DB1/ 147901903.2 154 Clause 66. The method of any one of clauses 47 to 65d, further comprising administering to the subject Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 66a. The method of any one of clauses 47 to 65d or 66, further comprising administering to the subject Compound 8:
Figure imgf000156_0001
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 67. The method of any one of clauses 47 to 66a, wherein the inflammatory disease/disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, and colitis. Clause 68. The method of any one of clauses 47 to 66a, wherein the AML is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML. Clause 69. The method of any one of clauses 47 to 66a or 68, wherein the subject has AML and the subject has a gene mutation in one or more of FLT3, TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, JAK2, ASXL1, ABL1, ATRX, BCORL1, KDM6A, PTPN11, TP53, CBL, CEBPA, FBXW7, HRAS, NRAS, IDH1, IDH2, NRAS, PDGFRA, SF3B1, ETV6, PHF6, GNAS, KRAS, NOTCH1, STAG2, SETBP1, GATA1, GATA2, WT1, SRSF2, GNAS, CEBPA, CALR, MPL, BCL11A, ATM, CTCF, U2AF1, TYK2, FBX, RUI, RAD21, or MLL3. DB1/ 147901903.2 155 Clause 70. The method of any one of clauses 47 to 66a, wherein the MDS is MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2. Clause 71. The method of any one of clauses 47 to 66a, wherein the subject has MDS and has a gene mutation in one or more of U2AF1, FLT3, ASXL1, BCORL1, BRAF, CBL, CDKN2A, DNMT3A, FBXW7, GATA2, IDH2, KRAS, NOTCH1, NRAS, PDGFRA, PTEN, PTPN11, TET2, TP53, EZH2, HRAS, KIT, MPL, PHF6, RUNX1, WT1, ABL1, CEBPA, ETV6, IDH2, KDM6A, KIT, KRAS, PTEN, RUNX1, SF3B1, or ZRSR2. Clause 72. The method of clause 71, wherein the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1, SRSF2, SF3B1, or ZRSR2. Clause 73. The method of any one of clauses 47 to 72, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has an IRAK1 IC50 of less than about 40 nM. Clause 73a. The method of any one of clauses 47 to 73, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of less than about 40 nM. Clause 74. The method of any one of clauses 47 to 72, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has an IRAK4 IC50 of less than about 5 nM. Clause 74a. The method of any one of clauses 47 to 72 or 74, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of less than about 5 nM. Clause 75. The method of any one of clauses 47 to 74a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, DB1/ 147901903.2 156 CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has IRAK4:IRAK1 potency ratio of less than about 40. Clause 75a. The method of any one of clauses 47 to 75, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has IRAK4:IRAK1 potency ratio of less than about 40. Clause 76. The method of any one of clauses 47 to 75a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has an FLT3 IC50 of less than about 2.5 nM. Clause 76a. The method of any one of clauses 47 to 76, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has an FLT3 IC50 of less than about 2.5 nM. Clause 77. The method of any one of clauses 47 to 76, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. Clause 77a. The method of any one of clauses 47 to 77, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. Clause 78. The method of any one of clauses 47 to 77a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject. DB1/ 147901903.2 157 Clause 78a. The method of any one of clauses 47 to 78, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject. Clause 79. The method of clause 78 or 78a, wherein the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. Clause 80. The method of any one of clauses 47 to 79, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject after the administration is stopped. Clause 80a. The method of any one of clauses 47 to 80, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject after the administration is stopped. Clause 81. The method of clause 80 or 80a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped. Clause 81a. The method of clause 80 or 81, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped. Clause 82. The method of any one of clauses 47 to 81a, wherein the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous DB1/ 147901903.2 158 administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. Clause 83. The method of any one of clauses 47 to 82, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is administered to the subject in a dosage of from about 0.35 mg to about 70,000 mg. Clause 83a. The method of any one of clauses 47 to 83, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight or Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in a dosage of from about 0.35 mg to about 70,000 mg. Clause 84. The method of any one of clauses 47 to 83a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR DB1/ 147901903.2 159 inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. Clause 84a. The method of any one of clauses 47 to 84, wherein Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. Clause 85. The method of clause 84 or 84a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound DB1/ 147901903.2 160 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. Clause 85a. The method of any one of clauses 84, 84a, or 85, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. Clause 86. The method of any one of clauses 84, 84a, 85, or 85a, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. Clause 87. The method of clause 86, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject. Clause 87a. The method of clause 86 or 87, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject. Clause 88. The method of clause 87 or 87a, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. DB1/ 147901903.2 161 Clause 88a. The method of any one of clauses 87, 87a, or 88, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 89. The method of clause 88 or 88a, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 89a. The method of any one of clauses 88, 88a, or 89, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 90. The method of any one of clauses 87 to 89a, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a DB1/ 147901903.2 162 pharmaceutically acceptable salt thereof, increases survival of the subject by treating AML in the subject. Clause 90a. The method of any one of clauses 87 to 89 or 90, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by treating AML in the subject. Clause 91. The method of any one of clauses 84, 84a, 85, or 85a, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof or acalabrutinib or a pharmaceutically acceptable salt. Clause 92. The method of any one of clauses 84, 84a, 85, or 85a, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof. Clause 93. The method of any one of clauses 84, 84a, 85, or 85a, wherein the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor. Clause 94. The method of clause 93, wherein the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof. Clause 95. The method of any one of clauses 84, 84a, 85, or 85a, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. Clause 101. A method of treating an inflammatory disease ordisorder, or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in a subject in need thereof, the method comprising administering to the subject Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 101a. The method of clause 101, wherein the method comprises administering to the subject Compound 8: DB1/ 147901903.2 163 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 102. The method of clause 101 or 101a, wherein the inflammatory disease or disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis. Clause 103. The method of clause 101 or 101a, wherein the AML is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML. Clause 104. The method of any one of clauses 101, or 101a, or 103, wherein the subject has AML and the subject has a gene mutation in one or more of FLT3, TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, JAK2, ASXL1, ABL1, ATRX, BCORL1, KDM6A, PTPN11, TP53, CBL, CEBPA, FBXW7, HRAS, NRAS, IDH1, IDH2, NRAS, PDGFRA, SF3B1, ETV6, PHF6, GNAS, KRAS, NOTCH1, STAG2, SETBP1, GATA1, GATA2, WT1, SRSF2, GNAS, CEBPA, CALR, MPL, BCL11A, ATM, CTCF, U2AF1, TYK2, FBX, RUI, RAD21, or MLL3. Clause 105. The method of clause 101 or 101a, wherein the MDS is MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2. Clause 106. The method of any one of clauses 101, 101a, or 105, wherein the subject has MDS and the subject has a gene mutation in one or more of U2AF1, FLT3, ASXL1, BCORL1, BRAF, CBL, CDKN2A, DNMT3A, FBXW7, GATA2, IDH2, KRAS, NOTCH1, NRAS, PDGFRA, PTEN, PTPN11, TET2, TP53, EZH2, HRAS, KIT, MPL, PHF6, RUNX1, WT1, ABL1, CEBPA, ETV6, IDH2, KDM6A, KIT, KRAS, PTEN, RUNX1, SF3B1, or ZRSR2. DB1/ 147901903.2 164 Clause 107. The method of clause 105, wherein the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1, SRSF2, SF3B1, or ZRSR2. Clause 108. The method of any one of clauses 101 to 107, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has an IRAK1 IC50 of less than about 40 nM. Clause 108a. The method of any one of clauses 101 to 107, or 108, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of less than about 40 nM. Clause 109. The method of any one of clauses 101 to 108a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has an IRAK4 IC50 of less than about 5 nM. Clause 109a. The method of any one of clauses 101 to 109, wherein Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of less than about 5 nM. Clause 110. The method of any one of clauses 101 to 109a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has IRAK4:IRAK1 potency ratio of less than about 40. Clause 110a. The method of any one of clauses 101 to 110, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has IRAK4:IRAK1 potency ratio of less than about 40. Clause 111. The method of any one of clauses 101 to 110a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has an FLT3 IC50 of less than about 2.5 nM. DB1/ 147901903.2 165 Clause 111a. The method of any one of clauses 101 to 111, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an FLT3 IC50 of less than about 2.5 nM. Clause 112. The method of any one of clauses 101 to 111a, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes and/or decreased expression of one or more IRAK1/4-associated genes. Clause 112a. The method of clause 112, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes compared to a healthy control subject and/or decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject. Clause 113. The method of clause 112 or 112a, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, DB1/ 147901903.2 166 GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, DB1/ 147901903.2 167 SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 114. The method of any one of clauses 112, 112a, or 113, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. Clause 115. The method of clause 112 or 112a, wherein the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, DB1/ 147901903.2 168 STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, DB1/ 147901903.2 169 METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 116. The method of any one of clauses 112, 112a, or 115, wherein the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. Clause 117. The method of any one of clauses 101 to 116, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the DB1/ 147901903.2 170 expression of one of more IRAK1/4-associated genes found to be elevated in the subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject. Clause 117a. The method of any one of clauses 101 to 117, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject. Clause 117b. The method of clause 117 or 117a, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof and/or wherein the administration of Compound 8 increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 117c. The method of any one of clauses 117 to 117b, wherein the administration of Compound 8 decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof and/or wherein the administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject before the administration of or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. DB1/ 147901903.2 171 Clause 117d. The method any one of clauses 117 to 117c, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more IRAK1/4- associated genes found to be decreased in the subject compared to a healthy control subject. Clause 117e. The method any one of clauses 117 to 117d, wherein the administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 117f. The method of any one of clauses 101 to 117, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one of more IRAK1/4-associated genes in the subject and/or increases the expression of one of more IRAK1/4-associated genes in the subject. Clause 118. The method of any one of clauses 117 to 117f, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, DB1/ 147901903.2 172 ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, DB1/ 147901903.2 173 LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7 IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject. Clause 118a. The method of any one of clauses 117 to 117e or 118, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, DB1/ 147901903.2 174 PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, DB1/ 147901903.2 175 JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7 IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject. Clause 119. The method of any one of clauses 117 to 117e, 118, or 118a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, DB1/ 147901903.2 176 SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 119a. The method of any one of clauses 117 to 117e, 118, 118a, or 119, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 120. The method of any one of clauses 117 to 117e, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, DB1/ 147901903.2 177 NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, DB1/ 147901903.2 178 NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7 IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject. Clause 120a. The method of any one of clauses 117 to 117e or 120, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, DB1/ 147901903.2 179 STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, DB1/ 147901903.2 180 LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7 IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject. Clause 121. The method of any one of clauses 117 to 117e, 120, or 120a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. DB1/ 147901903.2 181 Clause 121a. The method of any one of clauses 117 to 117e, 120, 120a, or 121 wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 122. The method of any one of clauses 101 to 121a, wherein the subject in need thereof has elevated expression of one or more NFκB-associated genes and/or decreased expression of one or more NFκB-associated genes. Clause 122a. The method of clause 122, wherein the subject in need thereof has elevated expression of one or more NFκB-associated genes compared to a healthy control subject and/or decreased expression of one or more NFκB-associated genes compared to a healthy control subject. Clause 123. The method of clause 122 or 122a, wherein the subject in need thereof has elevated expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, DB1/ 147901903.2 182 FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 124. The method of clause 122 or 122a, wherein the subject in need thereof has decreased expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, DB1/ 147901903.2 183 AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, DB1/ 147901903.2 184 SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 125. The method of any one of clauses 101 to 124, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one of more NFκB-associated genes found to be elevated in the subject and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject. Clause 125a. The method of any one of clauses 101 to 124, or 125, wherein the Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one of more NFκB-associated genes found to be elevated in the subject and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject. Clause 125b. The method clause 125 or 125a, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one of more NFκB-associated genes found to be elevated in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, DB1/ 147901903.2 185 Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 125c. The method any one of clauses 125 to 125b, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, decreases the expression of one of more NFκB-associated genes found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 125e. The method of any one of clauses 125 to 125d, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more NFκB-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 125f. The method of any one of clauses 125 to 125e, wherein the administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one of more NFκB-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 125g The method of any one of clauses 101 to 124, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, decreases the expression of one of more NFκB-associated genes in the subject and/or increases the expression of one of more NFκB-associated genes in the subject. Clause 126. The method of any one of clauses 125 to 125g, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound DB1/ 147901903.2 186 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, DB1/ 147901903.2 187 PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. Clause 126a. The method of any one of clauses 125 to 125g or 126, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, DB1/ 147901903.2 188 GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. Clause 127. The method of any one of clauses 125 to 125g, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof increases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, DB1/ 147901903.2 189 ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, DB1/ 147901903.2 190 SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. Clause 127a. The method of any one of clauses 125 to 125g or 127, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof increases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, DB1/ 147901903.2 191 IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. Clause 128. The method of any one of clauses 101 to 127a, wherein the subject in need thereof has elevated secretion of one or more cytokines. Clause 128a. The method of clause 128, wherein the subject in need thereof has elevated secretion of one or more cytokines compared to a healthy control subject. Clause 129. The method of clause 128 or 128a, wherein the subject in need thereof has elevated secretion of one or more cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ. Clause 130. The method of any one of clauses 101 to 129, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, DB1/ 147901903.2 192 or salt of an isomer of any one thereof decreases the secretion of one of more cytokines found to be elevated in the subject. Clause 130a. The method of any one of clauses 101 to 130, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the secretion of one of more cytokines found to be elevated in the subject. Clause 130b. The method of clause 130 or 130a, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the secretion of one of more cytokines found to be elevated in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 130c. The method of any one of clauses 130 to 130b, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the secretion of one of more cytokines found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 130d. The method any one of clauses 130 to 130c, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the secretion of one of more cytokines found to be elevated in the subject compared to a healthy control subject. Clause 130e. The method any one of clauses 130 to 130d, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the secretion of one of more cytokines found to be elevated in the subject compared to a healthy control subject. Clause 130f. The method of any one of clauses 101 to 129, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, DB1/ 147901903.2 193 optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the secretion of one of more cytokines in the subject. Clause 131. The method of any one of clauses 130 to 130f, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the secretion of one or more cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ in the subject. Clause 131a. The method of any one of clauses 130 to 130e or 131, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the secretion of one or more cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ in the subject. Clause 132. The method of any one of clauses 101 to 131a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. Clause 132a. Clause 132. The method of any one of clauses 101 to 132, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. Clause 133. The method of any one of clauses 101 to 132a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject. DB1/ 147901903.2 194 Clause 133a. The method of any one of clauses 101 to 133, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject. Clause 134. The method of clause 133 or 133a, wherein the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. Clause 135. The method of any one of clauses 101 to 134, wherein the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. Clause 136. The method of any one of clauses 101 to 135, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight or in a dosage of from about 0.35 mg to about 70,000 mg. Clause 136a. The method of any one of clauses 101 to 136, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight or in a dosage of from about 0.35 mg to about 70,000 mg. Clause 137. The method of any one of clauses 101 to 136a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is administered to the subject in a dosage of from about 1 µM to about 1,000 µM, optionally about 1 µM to about 50 µM. Clause 137a. The method of any one of clauses 101 to 137, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in a dosage of from about 1 µM to about 1,000 µM, optionally about 1 µM to about 50 µM. DB1/ 147901903.2 195 Clause 138. The method of any one of clauses 101 to 137a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is administered to the subject daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once a week, twice a month, or once a month. Clause 138a. The method of any one of clauses 101 to 138, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once a week, twice a month, or once a month. Clause 139. The method of any one of clauses 101 to 138a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof treats the inflammatory disease/disorder, AML, or MDS in the subject during the time period that the compound is administered to the subject. Clause 139a. The method of any one of clauses 101 to 139, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats the inflammatory disease/disorder, AML, or MDS in the subject during the time period that the compound is administered to the subject. Clause 140. The method of any one of clauses 101 to 139a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject after the administration is stopped. Clause 140a. The method of any one of clauses 101 to 140, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject after the administration is stopped. DB1/ 147901903.2 196 Clause 141. The method of clause 140 or 140a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA- 4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped. Clause 141a. The method of any one of clauses 140, 140a, or 141, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped. Clause 142. The method of any one of clauses 101 to 141a, further comprising administering to the subject one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF- 1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. DB1/ 147901903.2 197 Clause 143. The method of any one of clauses 101 to 142, further comprising administering to the subject at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. Clause 144. The method of clause 142 or 143, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. Clause 145. The method of clause 144, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases survival of the subject. Clause 145a. The method of clause 144, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject. Clause 146. The method of clause 145 or 145a, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, increases survival of the subject, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 146a. The method of any one of clauses 145, 145a, or 146, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 147. The method of clause 146 or 146a, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, DB1/ 147901903.2 198 Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 147a. The method of any one of clauses 146, 146a, or 147, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 148. The method of any one of clauses 145 to 147a, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by treating AML in the subject. Clause 148a. The method of any one of clauses 145 to 147a or 148, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by treating AML in the subject. Clause 149. The method of clause 142 or 143, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof or acalabrutinib or a pharmaceutically acceptable salt thereof. Clause 150. The method of clause 142 or 143, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof. DB1/ 147901903.2 199 Clause 151. The method of clause 142 or 143, wherein the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor. Clause 152. The method of clause 151, wherein the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof. Clause 153. The method of clause 142 or 143, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. Clause 154. A method of determining whether a subject with an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be treated by the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA- 4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof , the method comprising: determining whether the subject has elevated expression of one or more IRAK1/4-associated genes compared and/or decreased expression of one or more IRAK1/4-associated genes, wherein the IRAK1/4-associated genes are selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, DB1/ 147901903.2 200 ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, DB1/ 147901903.2 201 PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 154a. The method of clause 154, wherein the subject has elevated expression of one or more IRAK1/4-associated genes compared to a healthy control subject and/or a decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject. Clause 155. The method of clause 154 or 154a, wherein the IRAK1/4-associated genes are selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. Clause 156. The method of any one of clauses 154, 154a, or 155, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, DB1/ 147901903.2 202 MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, DB1/ 147901903.2 203 FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 157. The method of any one of clauses 154 to 156, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, DB1/ 147901903.2 204 LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. Clause 158. The method of clause 154 or 154a, wherein the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, DB1/ 147901903.2 205 KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, DB1/ 147901903.2 206 VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395. Clause 159. The method of any one of clauses 154, 154a, or 158, wherein the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3. Clause 160. The method of any one of clauses 154 to 159, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject. Clause 160a. The method of any one of clauses 154 to 160, wherein the administration of Compound 8, or salt of an isomer thereof decreases the expression of one of more IRAK1/4- associated genes found to be elevated in the subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject. Clause 160b. The method of clause 160 or 160a, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more IRAK1/4- associated genes found to be elevated in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, DB1/ 147901903.2 207 geometric isomer, or salt of an isomer of any one thereof and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 160c. The method of any one of clauses 160 or 160b, wherein the administration of Compound 8, or salt of an isomer of any decreases the expression of one of more IRAK1/4- associated genes found to be elevated in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 160d. The method of clause 160 or 160c, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 160e. The method of clause 160 or 160d, wherein the administration Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one of more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 161. The method of any one of clauses 160 to 160e, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one or more IRAK1/4- DB1/ 147901903.2 208 associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, DB1/ 147901903.2 209 CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject. DB1/ 147901903.2 210 Clause 161a. The method of any one of clauses 160 to 160e or 161, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, DB1/ 147901903.2 211 ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, DB1/ 147901903.2 212 HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject. Clause 162. The method of any one of clauses 160 to 160e, 161, or 161a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 162a. The method of any one of clauses 160 to 160e, 161, 161a, or 162 wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 163. The method of any one of clauses 160 to 160e, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof increases the expression of one or more IRAK1/4- associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, DB1/ 147901903.2 213 C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, DB1/ 147901903.2 214 FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject. Clause 163a. The method of any one of clauses 160 to 160e or 163, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof increases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, DB1/ 147901903.2 215 CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DB1/ 147901903.2 216 DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject. Clause 164. The method of any one of clauses 160 to 160e, 163, or 163a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, DB1/ 147901903.2 217 geometric isomer, or salt of an isomer of any one thereof increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 164a. The method of any one of clauses 160 to 160e, 163, 163a, or 164 wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. Clause 165. A method of determining whether a subject an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be treated by the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, the method comprising: determining whether the subject has elevated expression of one or more NFκB-associated genes and/or decreased expression of one or more NFκB-associated genes, wherein the NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, DB1/ 147901903.2 218 BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, DB1/ 147901903.2 219 THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 165a. The method of clause 165, wherein the subject has elevated expression of one or more NFκB-associated genes compared to a healthy control subject and/or a decreased expression of one or more NFκB-associated genes compared to a healthy control subject. Clause 166. The method of clause 165 or 165a, wherein the subject in need thereof has elevated expression of one or more NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, DB1/ 147901903.2 220 LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 167. The method of clause 165 or 165a, wherein the subject in need thereof has decreased expression of one or more NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, DB1/ 147901903.2 221 CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO- gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366. Clause 168. The method of any one of clauses 165 to 167, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound DB1/ 147901903.2 222 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more NFκB-associated genes found to be elevated in the subject and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject. Clause 168a. The method of any one of clauses 165 to 168, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one of more NFκB-associated genes found to be elevated in the subject and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject. Clause 168b. The method of clause 168 or 168a, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more NFκB-associated genes found to be elevated in the subject before the administration of Compound 8 and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject before the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 168c. The method of any one of clauses 168 to 168b, wherein the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one of more NFκB-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject compared to a healthy control subject. DB1/ 147901903.2 223 Clause 168d. The method of any one of clauses 168 to 168c, wherein the administration of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one of more NFκB-associated genes found to be elevated in the subject compared to a healthy control subject and/or increases the expression of one of more NFκB-associated genes found to be decreased in the subject compared to a healthy control subject. Clause 169. The method of any one of clauses 168 to 168d, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof decreases the expression of one or more NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, DB1/ 147901903.2 224 IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. Clause 169a. The method of any one of clauses 168 to 168d or 169, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof decreases the expression of one or more NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, DB1/ 147901903.2 225 CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, DB1/ 147901903.2 226 TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. Clause 170. The method of any one of clauses 168 to 168d, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof increases the expression of one or more NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, DB1/ 147901903.2 227 MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. Clause 170a. The method of any one of clauses 168 to 168d or 170, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof increases the expression of one or more NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, DB1/ 147901903.2 228 CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject. Clause 170b. A method of determining whether a subject with an inflammatory disease or disorder or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic DB1/ 147901903.2 229 syndrome (MDS) can be treated by the administration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA- 4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, the method comprising: determining whether the subject has elevated secretion of one or more cytokines, wherein the one or more cytokines are selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ. Clause 170c. The method of clause 170b, wherein the subject has elevated expression of one or more cytokines compared to a healthy control subject and/or a decreased expression of one or more cytokines compared to a healthy control subject. Clause 171. The method of any one of clauses 154 to 170c, further comprising administering to the subject Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof. Clause 171a. The method of any one of clauses 154 to 170c or 171, further comprising administering to the subject Compound 8:
Figure imgf000231_0001
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 172. The method of any one of clauses 154 to 171a, wherein the inflammatory disease or disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis. DB1/ 147901903.2 230 Clause 173. The method of any one of clauses 154 to 171a, wherein the AML is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML. Clause 174. The method of any one of clauses 154 to 171a or 173, wherein the subject has AML and the subject has a gene mutation in one or more of FLT3, TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, JAK2, ASXL1, ABL1, ATRX, BCORL1, KDM6A, PTPN11, TP53, CBL, CEBPA, FBXW7, HRAS, NRAS, IDH1, IDH2, NRAS, PDGFRA, SF3B1, ETV6, PHF6, GNAS, KRAS, NOTCH1, STAG2, SETBP1, GATA1, GATA2, WT1, SRSF2, GNAS, CEBPA, CALR, MPL, BCL11A, ATM, CTCF, U2AF1, TYK2, FBX, RUI, RAD21, or MLL3. Clause 175. The method of any one of clauses 154 to 171a, wherein the MDS is MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2. Clause 176. The method of any one of clauses 154 to 171a, wherein the subject has MDS and has a gene mutation in one or more of U2AF1, FLT3, ASXL1, BCORL1, BRAF, CBL, CDKN2A, DNMT3A, FBXW7, GATA2, IDH2, KRAS, NOTCH1, NRAS, PDGFRA, PTEN, PTPN11, TET2, TP53, EZH2, HRAS, KIT, MPL, PHF6, RUNX1, WT1, ABL1, CEBPA, ETV6, IDH2, KDM6A, KIT, KRAS, PTEN, RUNX1, SF3B1, or ZRSR2. Clause 177. The method of clause 176, wherein the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1, SRSF2, SF3B1, or ZRSR2. Clause 178. The method of any one of clauses 154 to 177, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has an IRAK1 IC50 of less than about 40 nM. Clause 178a. The method of any one of clauses 154 to 178, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK1 IC50 of less than about 40 nM. Clause 179. The method of any one of clauses 154 to 178a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound DB1/ 147901903.2 231 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has an IRAK4 IC50 of less than about 5 nM. Clause 179a. The method of any one of clauses 154 to 179, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an IRAK4 IC50 of less than about 5 nM. Clause 180. The method of any one of clauses 154 to 179, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has IRAK4:IRAK1 potency ratio of less than about 40. Clause 180a. The method of any one of clauses 154 to 180, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has IRAK4:IRAK1 potency ratio of less than about 40. Clause 181. The method of any one of clauses 154 to 180a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof has an FLT3 IC50 of less than about 2.5 nM. Clause 181a. The method of any one of clauses 154 to 181, wherein Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof has an FLT3 IC50 of less than about 2.5 nM. Clause 182. The method of any one of clauses 154 to 181a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. Clause 182a. The method of any one of clauses 154 to 182, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is more effective at DB1/ 147901903.2 232 inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. Clause 183. The method of any one of clauses 154 to 182a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof provides sustained treatment of the inflammatory disease ordisorder, AML, or MDS in the subject. Clause 183a. The method of any one of clauses 154 to 183, Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof provides sustained treatment of the inflammatory disease ordisorder, AML, or MDS in the subject. Clause 184. The method of clause 183 or 183a, wherein the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. Clause 185. The method of any one of clauses 154 to 184, wherein the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. Clause 186. The method of any one of clauses 154 to 185, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight or in a dosage of from about 0.35 mg to about 70,000 mg. Clause 186a. The method of any one of clauses 154 to 186, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight or in a dosage of from about 0.35 mg to about 70,000 mg. DB1/ 147901903.2 233 Clause 187. The method of any one of clauses 154 to 186a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is administered to the subject in a dosage of from about 1 µM to about 1,000 µM, optionally about 1 µM to about 50 µM. Clause 187a. The method of any one of clauses 154 to 187, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is administered to the subject in a dosage of from about 1 µM to about 1,000 µM, optionally about 1 µM to about 50 µM. Clause 188. The method of any one of clauses 154 to 187a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof is administered to the subject daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once a week, twice a month, or once a month. Clause 188a. The method of any one of clauses 154 to 188, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is administered to the subject daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once a week, twice a month, or once a month. Clause 189. The method of any one of clauses 154 to 188a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof treats the inflammatory disease/disorder, AML, or MDS in the subject during the time period that the compound is administered to the subject. Clause 189a. The method of any one of clauses 154 to 189, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof treats the inflammatory disease/disorder, AML, or MDS in the subject during the time period that the compound is administered to the subject. DB1/ 147901903.2 234 Clause 190. The method of any one of clauses 154 to 189a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject after the administration is stopped. Clause 190a. The method of any one of clauses 154 to 190, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject after the administration is stopped. Clause 191. The method of clause 190 or 190a, wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA- 4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped. Clause 191a. The method of clause 190 or 191, wherein Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof continues to treat the inflammatory disease/disorder, AML, or MDS in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped. Clause 192. The method of any one of clauses 171 to 191a, further comprising administering to the subject one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, DB1/ 147901903.2 235 a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF- 1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. Clause 192. The method of any one of clauses 171 to 191, further comprising administering to the subject at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. Clause 193. The method of clause 191 or 192, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. Clause 194. The method of clause 193, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject. Clause 194a. The method of clause 193 or 194, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject. Clause 195. The method of clause 194, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 1, Compound 2, Compound 3, DB1/ 147901903.2 236 Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 195a. The method of any one of clauses 194, 194a, or 195, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 196. The method of clause 195 or 195a, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 196a. The method of any one of clauses 195, 195a, or 196, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. Clause 197. The method of any one of clauses 194 to 196a, wherein the combination of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, DB1/ 147901903.2 237 Compound 14, Compound 15, CA-4948 (Emavusertib), R835, R289, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer of any one thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by treating AML in the subject. Clause 197a. The method of any one of clauses 194 to 196a or 197, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by treating AML in the subject. Clause 198. The method of clause 191 or 192, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof or acalabrutinib or a pharmaceutically acceptable salt thereof. Clause 199. The method of clause 191 or 192, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof. Clause 200. The method of clause 191 or 192, wherein the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor. Clause 201. The method of clause 200, wherein the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof. Clause 202. The method of clause 191 or 192, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. EXAMPLES Example 1: Inhibition of Both IRAK1 and IRAK4 is Required for Complete Suppression of NF- κB Signaling Across Multiple Receptor-Mediated Pathways in MDS and AML In this report, a pharmacological approach was used in which a series of IRAK inhibitors of varying relative potency at IRAK4:IRAK1 were examined for both inhibition of NF-kB activation in AML cells and inhibition of leukemic progenitor cell function in vitro. It was found that potency and efficacy for antagonism at NF-kB requires effective inhibition of both IRAK1 and IRAK4. It was also found that the relative potency of NF-kB inhibition correlates with suppression of leukemic progenitor cell function in vitro, providing pharmacological validation DB1/ 147901903.2 238 that inhibition of both IRAK1 and IRAK4 are necessary for optimal inhibition of NF-kB and effect on leukemia progenitor cell function. An NF-kB reporter system expressed in human AML cells (THP1) was used to measure NF-kB dependent activation in response to a variety of IRAK4, IRAK1, or IRAK1/4 antagonists. The cells are highly responsive to both TLR agonists as well as to IL-1β, which allows for measurement of IRAK-mediated antagonism of multiple receptor-mediated pathways. Using the IRAK4-selective antagonists PF-06650833 and BAY 1834845 it was found that both compounds fully suppress signaling through TLR2 (IC50 vs. Pam3CSK4 = 7.2 and 150 nM, respectively). The IRAK4 antagonists inhibit signaling through the IL-1R with similar relative potency (IC50 vs. IL-1β = 5.7 and 81 nM), but do not fully suppress signaling through this receptor (Span = 75% and 59%, respectively). Interestingly, the IRAK1 selective covalent inhibitor JH-X-119-01 does not inhibit signaling against either the TLR or the IL-1 receptor agonist. Together these data imply that neither IRAK4 nor IRAK1 inhibition alone is sufficient to fully inhibit NF-kB- mediated signaling through multiple receptor mediated pathways. For this reason, the activity of a series of IRAK4/IRAK1 inhibitors was examined in AML cells. This allowed for a study of the effect of adding in additional inhibitory activity at IRAK1 on the background of high potency IRAK4 inhibitors. Using two reference compounds with varying IRAK4:IRAK1 potency, the relative ability of these two compounds to inhibit TLR-agonist or IL-1β-agonist stimulated NF-kB activity in AML was compared. Compound 15 has an IRAK4:IRAK1 potency ratio of 36 whereas Compound 14 has an IRAK4:IRAK1 potency ratio of 100. Unlike what was observed with the IRAK4-selective antagonists, both compounds can completely suppress NF-kB signaling through IL-1β, with relative potencies apparently determined by their activity at IRAK1: (IC50 vs. Pam3CSK4 = 6.3 and 73.8 nM for Compound 15 and Compound 14, respectively); (IC50 vs. IL-1β = 9.3 and 227 nM for Compound 15 and Compound 14, respectively). Finally, the correlation between potency in the biochemical kinase assay at IRAK1 or IRAK4, activity in the NF-kB reporter assay, and leukemic progenitor cell activity in the colony forming assay was examined for a series of compounds. A correlation was found between kinase activity for both IRAK1 and IRAK4 and NF-kB activity that extends to the leukemia colony forming assays. This suggests that NF-kB signaling contributes to leukemia progenitor cell DB1/ 147901903.2 239 function and that optimal inhibition requires potent antagonism of both IRAK1 and IRAK4 in the setting of MDS and AML. See FIGS.1-7 and Table 1 for the data described in Example 1. DB1/ 147901903.2 240 0 5 O ) B W- 1 2 LI
Figure imgf000242_0001
1 ( 0 G 5- O 2 L 3 . 0 2 8 . 0 1 5 . 4 2 6 3 0 3 ) 1 M AP ( G O 8 0 0 L 3 . 2 9 . 1 5 . 2 )4 K A RI( G O 3 L 1 . 1 4 0 1 . 0 6 . 0 )1 K A RI( G O 2 7 3 3 0 8 L . 1 . 1 . 1 B k B 0 F 1 L 5 9 5 1 4 I C I 0 . 2 3 6 6 1 3 2 N 1-P H M 0 A 5 2 2 4 . 9 7 T P C I 2 7 1 3 4 K 0 0 5 0 0 0 o i A B R 5 I C I 3 . 1 3 . 0 1 4 . 4 n oit c 1 a K e A 0 5 8 . 3 6 R R I C I 2 . 5 1 . 2 2 6 1 2 d . n d d 2 . 1 u n u n u 3 0 9 e o l p o p o p 1 0 b m m 9 7 a o o mo 4 1 T C C C / 1 B D 0 5 O W-2 1 0 5 7 0 3 - 8 . 4 1 . 1 5 . 4 1 6 3 0 3 1 42 . 2 4 1 0 . 1 4 . 1 4 2 5 3 . 2 . 0 . 0 0 - 0 - 48 8 1 . 5 0 . 0 6 . 1 3. 6 3 . 2 4 7 5 2 3 3 2 3. 5 . 6 7 0 . 1 1 7 2 0 0 9 8 2 . 0 2 6 . 9 0 8 . 0 69 . 4 6 8 . 4 . 3 0 4 3 4 5 6 d n d 2 . u n d d o u n u n u 3 0 9 p o p o o 1 0 m p p o m m m 9 7 4 1 C o C o C o C / 1 B D 0 5 O W-2 1 0 5 8 7 1 4 - 1 . 1 7 . 4 . 9 . 4 1 1 1 6 3 0 3 1 25 . 0 5 0 8 . 1 1 . 4 1 2 . 1 0 2 . 9 0 0 - 1 . 3 . 7 0 0 - 1 . 0 91 3 2 2 . 4 . 3 . 5 0 1 1 . 1 1. 7 9 3 5 . . 1 8 5 5 5 . 4 2 7 8 2 3 9 . . 2 . 3 3 2 6 4 . 1 7 1 7 3 0 6 . 4 0 0 5 . 0 0 1 5 . 9 0 4 . 1 45 . 2 . 1 7 2 1 2 3 3 7 8 9 d 2 n d . u n d o u n u 3 0 9 p o p o p 1 0 m m m 9 7 o C o C o 4 C 1 / 1 B D 0 5 O W-2 1 0 5 2 - 6 . 9 6 . 9 1 . 6 7 . 1 9 . 3 8 . 4 2 1 1 2 1 2 6 3 0 3 1 54 . 9 2 0 . 3 1 1 . 9 1 4 . 8 2 1 . 0 2 7 . 2 87 3 8 7 9 2 4 3 9 8 9 2 . 3 0 0 . 1 . 9 2 6 0 0 - 4 . 1 0 . . 1 0 - 43 7 2 . 1 0 4 2 2 . 1 . 1 . 3 9 8 4 2 4 1 . 4 8 . 4 5 0 1 8 . 8 4 5 1 8 7 6 2 0 2 8 . 6 2 . 3 7 0 6 2 1 1 0 3 5 1 9 4 0 7 0 6 . 6 7 2 2 . 7 1 0 . 1 7 . 0 1 . 3 0 1 2 . 0 0 2 7 . 7 2 4 4 . 5 1 0 1 7 1 A A N N )bi t r e s u v 0 a 1 1 1 2 1 3 1 m 5 3 d n d E u n d n d n ( 4 8 3 4 8 2 . 3 o u p o u o u o 8 4 3 0 9 8 5 6 0 9 1 m p p p o m m m 4 - 1 Y 6 0 0 9 - 7 4 C o C o C o C A C A B F P 1 / 1 B D Example 2: Introduction Leukemic cells exhibit dysregulation of innate immune signaling pathways upon diagnosis, and these pathways become further activated in drug resistance. The Interleukin-1 receptor associated kinase 1 and 4 (IRAK1/IRAK4) kinase complex is part of a critical signaling node that becomes activated in these dysregulated pathways (reviewed in J Bennett and DT Starczynowski, Curr Opin Hematol 2022). IRAK1 and IRAK4 utilize distinct and overlapping signaling pathways wherein IRAK1 compensates for IRAK4 inhibition in the setting of leukemia. Therefore, IRAK4 inhibition is insufficient for full efficacy in the setting of leukemia. The IRAK4 inhibitors are currently under investigation for the treatment of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) and have shown encouraging, though modest responses in clinical studies. It has recently been demonstrated that limited responses to IRAK4 inhibitors in the leukemic setting can be explained by a compensated upregulation and activation of IRAK1, and the need to inhibit both IRAK1 and IRAK4 to achieve maximal therapeutic efficacy (JR Bennett et. al., Blood 2023 https://doi.org/10.1182/blood.2022018718). Methods IRAK1/4 expression was determined by IP-MS (FIG.8A). Peptides were identified that were capable of quantitating IRAK4 total, IRAK4-Long versus IRAK4-Short, and IRAK1 proteins. The method, accuracy, and precision of each peptide has been qualified (IRAK1 LoQ = 5 ng/mL; IRAK4 LoQ = 10 ng/mL). Stable isotope labelled controls were used. Healthy PBMC expression levels were found to be: IRAK1 ~ 5-7 ng/mL; IRAK4 ~ 20-35 ng/mL. Hybrid LCMS (Immunoaffinity LC-MS/MS), also called Affinity-Capture LCMS was used to combine a selective enrichment step (typically an antibody enrichment on beads or columns) with the selectivity and sensitivity provided by LC-MS/MS (FIG.8B). For the colony forming assay data, viable AML primary patient cells were thawed and added to Methocult media containing at least (IL-3, GM-CSF and SCF) at a density of either 2 x 105 or 1 x 106 cells/culture. Then, either Compound 8, CA-4948 (emavusertib), a negative control of (DMSO) or Cytarabine, or 5-FU (positive control) was added to appropriate tube. Compound 8 was plated at concentrations between 0.2 µM and 5 µM in FLT3 wild type (WT) samples and at concentrations between 1 nM and 200 nM for FLT3 mutants. CA-4948 was DB1/ 147901903.2 245 plated at concentrations between 1 µM and 50 µM. Then the mixture was vortexed and plated at least in duplicates. Plates were incubated in a tissue culture incubator at 37 °C and supplemented with 5% CO2 for 10-16 days. Next, the colonies were imaged and analyzed. Cells for CFC (Colony Forming Cell) Progenitor Assays: Clonogenic progenitors of human AML-blast CFC were set up in a methylcellulose-based assay. Human bone marrow mononuclear cells from forty-seven four distinct AML patients which were either FLT3 wild type or FLT3 mutant were stored in the gaseous phase of liquid nitrogen. On each the day of the experiment, batches of 6-8 vials were thawed rapidly, the contents of each vial were diluted in 10 mL of Iscove’s modified Dulbecco’s medium containing 10% fetal bovine serum (IMDM + 10% FBS) and washed by centrifugation (approximately 1500 r.p.m. for 10 minutes, room temperature). The supernatant was discarded and the cell pellets for each donor were resuspended in a known volume of IMDM + 10% FBS. A cell count (3% glacial acetic acid) and viability assessment (trypan blue exclusion test) was performed for each bone marrow sample. A sample of cells (2 x 106) from each of the donors was snap frozen and retained at -80oC and subsequently sent to a third-party lab for additional analyses. In this semi-solid methylcellulose- based matrix, a series of compounds were evaluated for their effects on acute myeloid leukemia. Of the forty-seven AML marrow samples tested, seventeen AML marrow samples, 8 derived from FLT3 mutants and 9 from FLT3 WT supported clonal growth. Based on whether the AML patients were characterized as FLT3 mutants or wild types, they were treated with various compounds. The test compounds were added to the methylcellulose and the tubes vortexed to ensure equal distribution of the test compounds throughout the matrix. Bone marrow cells from all 47 AML patients were added to the tubes of methylcellulose and vortexed. Triplicate cultures were initiated in 35 mm dishes and dispensed by positive displacement. The cultures were incubated for 14 days. AML-blast CFC were assessed microscopically and scored by trained personnel in situ. Compounds: Three test compounds (Compound 8, CA-4948, and Gilteritinib) were received as 10 mM stocks. The FLT3 WT samples were treated with Compound 8 at 5, 1, and 0.2 µM. To achieve these concentrations, the 10 mL stock was diluted 1:1 with DMSO to generate a 5 mM stock and then serial 1:5 dilutions were prepared again in DMSO to generate 1 and 0.2 mM working stocks that were 1000 X the required testing concentration. When the working stock concentrations were added 1:1000 v/v to the methylcellulose-based medium, the DB1/ 147901903.2 246 final desired concentrations were achieved. To achieve 30 µM of CA4948, 13.2 µL of the 10 mM stock was added. To achieve 110 µM of CA4948, 4.4 µL of the 10 mM stock was added and to achieve the 0.1 µM CA4948, a 1:10 dilution of the 10 mM stock was made in DMSO and 4.4 µL of the 1.0 mM stock was added. DMSO was added as the solvent control for the WT AML-blast CFC assay at 0.3% final volume. The mutant AML samples were treated with both Compound 8 and Gilteritinib at 200, 20, and 2 nM. Stock concentrations of 200, 20, and 2 µM working stocks were prepared from the original 10 mM stocks and when these working stock concentrations were added 1:1000 v/v to the methylcellulose-based medium, the final desired concentrations were achieved. DMSO was added as the solvent control for the mutant AML- blast CFC assay at 0.1% final volume. NF-κB Reporter assay: Performed according to THP-1-Blue NF-κB cells and QUANTI- Blue reagent manufacturing protocol (InvivoGen). Colony forming units (CFU): Primary AML patient samples were obtained from Discovery life Sciences (DLS) and tested in a methylcellulose assay. Biochemical and Cell-based Kinase inhibitory assays: Kinase inhibitory data and cell- based kinase assays were obtained using the RBC HotSpot® Kinase and NANOBRET® Assay, respectively. The binding kinetics assay was performed using KINETICfinder® TR-FRET assay. Xenograft: Survival analysis was performed in NSG-SGM3 mice xenografted with MOLM14 FLT3-ITD (D835Y) cells. RNASeq: THP-1 cells were treated in liquid culture for 24 hr. Total RNA was extracted and RNAseq was performed at 30M reads per sample. Statistical analysis: All data were plotted using Graphpad Prism, and statistical significance was determined using T-test. Results and Discussion Compound 8 is a highly potent IRAK1/IRAK4/panFLT3 inhibitor that exhibits superior potency and therapeutic efficacy vs. IRAK4 inhibitor compounds in the FLT3 WT as well as the FLT3 mutant setting. Compound 8 exhibited >100-fold selectivity vs.89% of the Kinome as measured in the Reaction Biology 374 kinase panel (FIG.9), with an IC50 of 23, <1.29, and <0.5nM at IRAK1, IRAK4, and FLT3 respectively. Higher kinase selectivity was seen in cell-based assays vs. DB1/ 147901903.2 247 biochemical assays, where high potency kinase antagonist activity was also observed against PHKg1, PDGFRβ, RET, CLK1, and CLK4 (Table 2). Table 2. Data demonstrating the high on-target activity of Compound 8 and only 7 off-targets with <100 nM cell-based activity or high residence time Kinase Biochemical IC50 Cell-Based IC50 Residence Time t (nM) (nM) (min) IRAK1 24.8 Not tested 0.1 IRAK4 <1.31 <0.5 22 FLT3 <0.5 <0.5 73 PHKg1 5 <0.5 Not tested PHKg2 82 Not tested Not tested PDGFRα 19 Not tested Not tested PDGFRβ 56 18 0.27 RET 25 84 1.6 CLK1 55 33 1.5 CLK4 70 1 3.7 While IRAK4-selective compounds fully antagonize NF-κB signaling through the TLR pathway, Compound 8 completely inhibited NF-κB signaling through both the TLR and IL1- receptor pathways, indicating complete inhibition of multiple receptor pathways converging on NF-κB requires both IRAK1 and IRAK4 antagonism. FIG.10 depicts the antagonism of the NF- κB response of PAM3CSK4 through the TLR2 receptor (top) and the antagonism of the NF-κB response of IL-1β through the IL-1 receptor (bottom), wherein the error bars represent SEM from triplicate replicates. The experiment was replicated two additional times with similar results. Complete antagonism of signaling through both receptor pathways is only seen with the IRAK1/4 inhibitor (Compound 8). Principle Component Analysis (PCA) FIGS.11A-11C demonstrate that Compound 8 suppresses NF-κB and IRAK1/4- dependent signaling in AML cells. THP-1 cells were incubated for 24 hours with DMSO, three different concentrations of Compound 8, or two different concentrations of CA-4948 (emavusertib). Three biological replicates of each sample were prepared. RNA extraction and RNA sequencing was performed, where the libraries were sequenced at 30 M reads and the RNA quality number of all samples was between 9.8 and 10. FIG.11A is a principal component analysis (PCA) plot showing the variation between samples. Reads were aligned with STAR DB1/ 147901903.2 248 (Spliced Transcripts Alignment to a Reference) and counted with featureCounts (package: subread) to obtain gene-level quantifications. Alignment rates were above 70% in all experiments. FIGS.11B-11C are plots of showing the Z-score (blue downregulated, red upregulated) of the relative expression of NF-κB target genes (FIG.11B, genes listed in Table 4 of Appendix A) and IRAK1/4 dependency genes (FIG.11C, genes listed in Table 5 of Appendix A). Differentially Expressed Genes (DEGs) Versus Drug Concentration DEGs were calculated by comparison against control samples wherein Compound 8 was found to show effects at lower concentrations than CA-4948 (emavusertib) (FIG.12 and Table 3). FIGS.13A-13C provide charts of DEGs for controls versus different concentrations of Compound 8 and CA-4948. FIGS.14A-14C provide Venn diagrams showing overlapping DEGs (top) and charts of common DEGs (bottom) for 10 µM CA-4948 and 1 µM Compound 8 (FIG. 14A), 10 µM CA-4948 and 5 µM Compound 8 (FIG.14B), and 1 µM Compound 8 and 5 µM Compound 8 (FIG.14C). FIGS.15A-15B depict canonical NfkB target genes. FIGS.16A-16B depict signature genes on Compound 8 (FIG.16A) and their fold change (FIG 16B). FIG.17 provides a short IRAK1/4 signature for Compound 8 (by Z-score), with the genes listed in Table 6 of Appendix A. Table 3. Group Sample DEGs 200 nM Compound 8 0 1 µM Compound 8 3 Up DEGs 5 µM Compound 8 465 1 µM CA-4948 1 10 µM CA-4948 15 200 nM Compound 8 0 1 µM Compound 8 12 Down DEGs 5 µM Compound 8 736 1 µM CA-4948 0 10 µM CA-4948 21 AML Blast Colony Forming Unit (CFU) Data To obtain the AML blast CFU data, 50 primary AML PBMC samples were obtained, including 25 FLT3 mutant samples (23 samples received and plated; 7 grew colonies (meets expected 30-40% growth rate)) and 25 FLT3 WT samples (24 samples plated; 9 grew colonies DB1/ 147901903.2 249 (meets expected 30-40% growth rate)). 2-3 x 106 cells of each patient sample was pelleted for IRAK expression and genetic analysis. In THP-1 and MDSL FLT3 wildtype cultured cells as well as MOLM14 (D835Y) mutant cultured cells, Compound 8 inhibited leukemia stem cell progenitor function as measured by the colony formation assay in methylcellulose with higher potency than IRAK4 inhibitor compounds that lack IRAK1 activity such as CA-4948 (Emavusertib) (FIGS.18 and 20, respectively). Similarly, in primary patient cell lines from FLT3 wildtype (WT) and mutant patients, Compound 8 inhibited leukemia stem cell progenitor function as measured by the colony formation assay in methylcellulose with higher potency than IRAK4 inhibitor compounds that lack IRAK1 activity such as CA-4948 (Emavusertib) (FIGS.19A-19F: FLT3 wildtype patients, FIGS.21A-21B: FLT3 mutant patients). This activity was independent of patient mutational status. Importantly, high potency in primary patient cell lines was observed independent of the presence of U2AF1 or SF3B1 spliceosome mutations known to drive expression of the activated IRAK4 Long isoform of IRAK4 (FIGS.19A-19F and FIGS.21A-21B), implying that the IRAK1/4/panFLT3 inhibitor Compound 8 will have activity across a broader patient population than an IRAK4 inhibitor. The methylcellulose colony forming assay is a surrogate in vitro progenitor cell assay that allows for the evaluation of effect on progenitor cell function. Potency was found to be higher in the cultured cell line overexpressing the FLT3 double mutant (ITD, D835Y) versus the primary patient cell lines. Although not wishing to be limited by theory, it is believed that this is due to the level of receptor overexpression and the FLT3 mutant copy number variability in patient samples. The potency of Compound 8 was found to be greater than or equal to gilteritinib in the patient cell lines. An IRAK1/4 gene signature was previously described that is highly expressed in patients with myelomonocytic subtypes (M4 FAB) of adult and pediatric AML and with an antecedent MDS (JR Bennett et. al., Blood 2023 https://doi.org/10.1182/blood.2022018718) (FIGS.22A- 22B). The IRAK1/4 gene signature is reversed after treatment of THP1 cells for 24 hours with Compound 8. Given that monocytic-like subtypes of AML are resistant to Venetoclax plus Azacitidine (VEN/AZA) (S Pei et. al. Cancer Discovery, 2020), these data suggest that Compound 8 has the potential to be effective across a broader range of relapsed/refractory AML/MDS patients than previously examined IRAK4 inhibitors. DB1/ 147901903.2 250 A variety of primary patient cell lines were evaluated in colony forming assays in multiple sites. This assay measures leukemia stem cell progenitor cell function. When plated in methylcellulose, leukemic progenitor cells grow out and form colonies. Drugs are evaluated for inhibition of colony formation. The methylcellulose colony forming assay is a surrogate in vitro progenitor cell assay that allows for the evaluation of effect on progenitor cell function. However, AML patient cell lines are known to not grow well in methylcellulose. The success rate for colony formation with patient cell lines is ~30%, which is what was observed in these studies. Patient cell lines from FLT3 mutant or FLT3 WT AML patients were chosen. The comparator for the FLT3 mutant cell lines is Gilteritinib/Xospata® and the comparator for the FLT3 WT cell lines is CA-4948/Emavusertib®. All patients were evaluated for known mutations at diagnosis. Those mutations were associated with the primary patient cell lines when they were obtained from the patients (run on samples upon first collection) and were identified using next-generation sequencing (NGS) via the TruSight™ Myeloid Sequencing Panel (illumina®). Illustrated mutations associated with each patient cell line are indicated in the figures under the cell line identifier (FLT3 wildtype: FIGS.23A-23I; FLT3 mutant: FIGS.24A- 24G). The colony forming assays demonstrated that Compound 8 was more potent than CA- 4948/emavusertib in every FLT3 WT cell line evaluated. Compound 8 was found to be active in all primary patient cell lines that could be evaluated (i.e., that formed colonies), and potent activity was observed regardless of patient mutational status. Compound 8 was found to be about equipotent to, or more potent than, gilteritinib in the FLT3 mutant setting. Compound 8 was found to have high potency in the colony forming assay regardless of whether the cell line has a PDGFR mutation. Where FAB classification was available, the M4 patients appeared to have the highest potency for Compound 8. Although not wishing to be limited by theory, it appears as though Compound 8 had high potency in FLT3 wild type patients with a TP53 mutation. There are currently no drugs that successfully treat these patients. In about ¾ of the FLT3 wild type lines in the recent primary patient data set, the IC50 for Compound 8 is < 250nM. This is more potent than what has been seen for Compound 8 in the THP-1 and MDSL cells. Complete inhibition of colony formation (a measure of leukemic progenitor cell function) was observed in all four cell lines with Compound 8. DB1/ 147901903.2 251 Compound 8 was found to potently inhibit leukemic stem cell progenitor function regardless of mutational status. Compound 8 was found to suppress colony formation in primary AML patient samples. FIG.25A provides a comparison between % inhibition of colony formation (calculated as # treated colonies divided by # DMSO control colony growth) at 200 nM of Compound 8 across primary patient samples that are either wildtype (WT) or mutant for FLT3. No significant difference in response to inhibitor was observed between WT and FLT3 mutant samples, suggesting that similar drug doses can be used in both FLT3 WT and FLT3 mutant patient population (statistical analysis shown in FIG.25C). FIG.25D provides a mutational status of the corresponding FLT3 WT patient AML primary bone marrow blasts. *Similar mutational profiles were seen in FLT3 mutant AML patient samples (data not shown). Oral Dosing in Animals Compound 8 exhibited superior potency and efficacy to gilteritinib in the FLT3-ITD (D835Y) xenograft model after QD oral dosing, with sufficient PK and oral bioavailability across multiple species to support QD or BID dosing in the clinic. Compound 8 did not inhibit any of the major or minor cytochrome P450 enzymes at anticipated clinical concentrations and early indication from ongoing GLP toxicology studies suggest that it could be safely administered in humans. Compound 8 was also found to have an optimized preclinical safety profile. Metabolism yielded no active metabolites and no CYP3A4 interactions. At ion channel hERG (human ether-a-go-go related gene), Nav1.5, and Cav1.2, Compound 8 was found to have an IC50 of 7, 8, and >30 µM, respectively. In cardiovascular (CV) safety studies, Compound 8 was found to have no effect on beat rate, FPDc (heart rate-corrected field potential duration) (≈QTc (heart rate-corrected QT interval)) and no EADs (early after depolarizations (torsadogenic potential) in human iPSC-CMs (human induced-pluripotent stem cell cardiomyocytes) to 10 µM. Compound 8 was also found to have no effect on QTc in guinea pig cardiovascular function (ECG) to high dose ~25x mouse AUCeff and yielded no changes in function or structure in rat echocardiography to high dose ~44x mouse AUCeff. There were also no ECG (QT, QTc, HR) or BP (blood pressure) findings in single dose GLP Dog CV study to high dose ~11x mouse AUCeff. 5 mg/kg of Compound 8 was administered to an animal AML model wherein animals treated with Compound 8 were found to have higher survival than control animals (33 treated animals survived versus 12 control animals) (FIG.26). The animals treated with 5 mg/kg of DB1/ 147901903.2 252 Compound 8 also demonstrated higher survival than those treated with 35 mg/kg venetoclax. Additionally, animals treated with a combination of 5 mg/kg of Compound 8 and 35 mg/kg of venetoclax were found have higher survival than animals treated with either 5 mg/kg of Compound 8 alone (33 animals treated with Compound 8 alone survived versus 40 animals treated with the combination of Compound 8 and venetoclax) or 35 mg/kg of venetoclax alone (16 animals treated with venetoclax alone survived versus 40 animals treated with the combination of Compound 8 and venetoclax). Compound 8 demonstrated superior activity in vivo compared to benchmark compounds. Compound 8 was found to prolong survival in mice xenografted with MOLM14 FLT3-ITD (D835Y) (FIG.27). Survival was maintained even after withdrawal of Compound 8. Superior efficacy in reducing AML burden of Compound 8 was also observed relative to either Gilteritinib and CA-4948 (data not shown). These results are not explained solely by difference in plasma levels or occupancy at FLT3-ITD D835Y. Compound 8 was also found to exhibit high oral bio-availability across multiple species. Compound 8 was found to have high oral bioavailability, moderate clearance, and good oral exposure in mouse, rat, and dog (Table 4). Table 4. Pharmacokinetics of Compound 8 in multiple species Clearance rate AUC Cmax Half-life Oral bio- Species Dose (IV/PO) (mg/kg) (mL/min/kg) (nM*h) (nM) (h) availability (F%)* Rat 1/3 44 1861 319 2 76% Dog 1/3 19 3477 467 5.4 64% Mouse 1/10 177 3901 405 2.16 100% Mouse N.D./30 22621 1973 N/A * F - Fraction Example 3: In Vitro Evaluation of Compound 8 on Cytokine Secretion in PBMCs from Three Normal Human Donors pre-treated with Dynabeads or Pam3CSK4 Summary This experiment assessed the effect of Compound 8 on cytokine secretion in PBMCs from three normal donors, which were pre-treated with Dynabeads CD28-CD3 which stimulates the adaptive response or Pam3CSK4 which stimulates through innate immune signaling networks by binding Toll-like receptors. Variation was seen between donors, but this was an DB1/ 147901903.2 253 expected finding (Romer et al, 2001). Treatment with Dynabeads or Pam3CSK4 induced a number of cytokines in all donors, though Donor 3 had much less induction in response to Pam3CSK4. When Compound 8 was added to the PBMCs stimulated with Dynabeads, there was a significant reduction in multiple cytokines and again this varied between donors. However, there was a trend whereby if the Dynabeads induced cytokine secretion in a given donor, Compound 8 at 10 µM reduced this induction in almost all cases. Compound 8 at 1 µM had less impact. In many cases where the cytokine secretion was induced by dynabeads, Crisaborole reduced the amount with one exception of IL-8 where there was no reduction in any donor. When Compound 8 was added to the PBMCs stimulated with Pam3CSK4, there was a significant reduction in multiple cytokines and again this varied between donors. Once again, there was a trend whereby if Pam3CSK4 induced cytokine secretion in a given donor, Compound 8 at 10 µM reduced this induction in almost all cases. Interestingly, Compound 8 at 1 µM in Pam3CSK4 stimulated PBMCs also had a significant effect, reducing cytokine levels in almost all cases. Crisaborole in the Pam3CSK4 stimulated PBMCs reduced IL-10 and TNFα in all three donors and additionally GM-CSF, IL-1β, IL-17A and IL-23 in Donor 1. Cell viability was never compromised in any of the treatment conditions, therefore changes in cytokine levels are due to compound activity and not cell death. Terminology and Definitions rh: recombinant human TNF-α: Tumor Necrosis Factor- alpha IL-1 β: Interleukin 1 beta IL-2: Interleukin 2 IL-4: Interleukin 4 IL-5 : Interleukin 5 IL-6: Interleukin 6 IL-10 : Interleukin 10 IL-12 : Interleukin 12 IL-13 : Interleukin 13 IL-17: interleukin 17 IL-23: interleukin 23 GM-CSF : Granulocyte macrophage colony stimulating factor DB1/ 147901903.2 254 IFN-γ: Interferon gamma PBMC: peripheral blood mononuclear cells PBS: phosphate buffered saline FBS: fetal bovine serum mins: minutes r.p.m. revolutions per minute HI: heat inactivated OOR: out of range IRB: Institutional Review Board Table 5. Reagent list Reagent Vendor Cat. No. Lot no. Heparin Sigma H3149-50KU SLCN9941 Ficoll StemCell Technologies 7851 00222 RPMI Gibco 21870-076 2522735 FBS Peak Serum 01J1211 PS-FBI Crisaborole Selleckchem S5014 S501401 Dynabeads (CD3/CD28) Gibco 11131D 01266483 Pam3CSK4 InvivoGen tlrl-pms 5930-44-05 PBS Gibco 14190-144 2560969 DAPI Biolegend 422801 B358421 Table 6. Donor Information Donor # Gender Age Race Blood Type Other Notes 1 Male 25 Caucasian AB Pos CMV Pos 2 Male 48 Caucasian O Neg CMV Neg 3 Female 63 Caucasian O Pos CMV Pos Purpose The aim of the study was to evaluate cytokine secretion in response to Compound 8 and controls in PBMCs and whole blood derived from three normal human donors. Tests performed Cytokine secretion (TNFα, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFNƴ) was evaluated in response to Compound 8 and controls in PBMC. Preparation of PBMCs DB1/ 147901903.2 255 Fresh blood was acquired from Bloodworks within 4 hours of collection. The donors were fully consented, and the blood was collected under IRB approval. The fresh blood samples were diluted with an equal volume of PBS + 2% FBS and layered over ficoll (Lymphoprep). The tubes were placed in the centrifuge at a speed of 1200 r.p.m. with the brake set to the “off” position. PBMCs were harvested from the buffy layer and transferred to a new tube and washed with PBS + 2% FBS. The cells were then resuspended in RPMI + 10% HI-FBS, the cells were counted manually using glacial acetic acid and a Neubauer hemacytometer and then, to each well of a 96-well plate, 100,000 cells were added. Test Articles and Controls Compound 8 was provided in solution (10 mM). For the PBMC assay, working stocks were made in RPMI + 10% HI-FBS to generate concentrations of 200 and 20 µM. Additionally working stocks of Crisaborole were prepared at 200 µM. When added in at 1: 20 v/v, the desired test concentrations of Compound 8 were 10 and 1 µM and for Crisaborole was 10 µM. Method Summary PBMC Assay Format Fresh human blood was obtained from 3 normal human donors and PBMCs were prepared as described above. Once the cells had been prepared, three cell stocks were generated for Dynabeads-stimulated, Pam3CSK4-stimulated and unstimulated controls. For Dynabeads treated cells, a cell stock at 1.06 x 10^6/mL was mixed with equal volume of Dynabeads resuspended in RPMI + 10% HI-FBS (1:1 cells to beads ratio) and then 190 µL were added wells of a 96-well plate (100,000 cells/well). Similarly, for Pam3CSK4 treated cells, a cell stock at 1.06 x 10^6/mL was mixed with equal volume of Pam3CSK4 at 20 ng/mL in RPMI + 10% HI- FBS (Pam3CSK4 final concentration at 10 ng/mL) and then 190 µL were added wells (100,000 cells/well). For un-stimulated control cells, a cell stock at 0.53 x 10^6/mL was prepared and 190 µL were added to wells (100,000 cells/well). Test article Compound 8 and Crisaborole were prepared as described above, when 10 µL were added to 190 µL cells, the desired test concentrations were achieved. PBS was added to the exterior wells of the 96-well plate to retain a high and equal humidity. The content of cells and compounds were mixed and incubated at 37°C, 5% CO2 for 48 hours. After the 48-hour incubation, supernatants were harvested (170 µL) and divided between a well (95 µL) or an Eppendorf tube (75µL). The supernatants in the wells were retained at -80oC for backups and the supernatants in the Eppendorf tubes were coded and sent to Eve Technologies for cytokine analyses using the Luminex platform. The cytokines DB1/ 147901903.2 256 evaluated included GM-CSF, IFNy, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL- 17A, IL-23 and TNFα. Following removal of the supernatants for cytokine analyses, the cells were resuspended in PBS containing 2% FBS and stained with DAPI for cell viability assessed by flow cytometer. Statistical Analyses of Data For each condition triplicate tests were performed. Cytokine analyses were assessed using the Luminex platform. Where mean and standard deviations are reported, the values used to generate these numbers did not include values that were below the limits of quantitation. Where a value was OOO<, the value for the lower limit of detection for a given cytokine was used and where the value was OOO>, the upper limit of quantitation was used in order to get a significant value. In this analysis, the Dynabead, Pam3CSK4 or Compound 8 alone treated cultures were compared with unstimulated cultures whereas the Compound 8 cocultures with the Dynabeads or Pam3CSK4 were compared with Dynabeads or Pam2CSK4 alone cultures. Due to the potential subjectivity of cytokine release, a p value of less than 0.01 is deemed significant. Results The results of experiments to evaluate the potential effect of Compound 8 on secretion of cytokines in stimulated PBMC (Dynabeads or Pam3CSK4) and controls (Crisaborole) are presented in Tables 7-9 and cell viability data for each test article on each donor is presented in Table 10. The viability data served to confirm that the PBMCs remained viable over the course of the experiment and therefore any changes in cytokine secretion is due solely to the activity of the test articles and not cell death. Compound 8 when added to the PBMC (concentration range 10 and 1 µM) had no impact of cell viability. Pre-treatment of PBMCs with CD3-CD28 Dynabeads induced increases in multiple cytokines in all donors, when compared to the unstimulated controls but the extent of the increase and the actual cytokines varied between donors. Donor 2 exhibited the least amount of stimulation but increases in TNFα, IL-4, IL-5, IL-8 and IL-13 were consistent across all three donors (Tables 6-8). Pam3CSK4 only induced IL-10 in Donor 3 (Table 9) but GM-CSF, IL-β, IL-6, IL-8, IL-10, IL-17A, IL-23 and TNFα in Donor 1 and fewer cytokines (IL-6, IL-8, IL-10 and TNFα) in Donor 2 (Tables 7 and 8). Compound 8 treatment alone did not induce any cytokines when compared to the unstimulated controls (Tables 7-9). DB1/ 147901903.2 257 When Compound 8 was added to the PBMCs stimulated with Dynabeads, there was a significant reduction in multiple cytokines and again this varied between donors. However, there was a trend whereby if the Dynabeads induced cytokine secretion in a given donor, Compound 8 at 10 µM reduced this induction in almost all cases. Compound 8 at 1 µM had less impact, but reduced IL-1β, IL-6, IL-13, IL-17A and TNFα in Donor 1, IL-8 and IL-13 in Donor 2 and IL-1, IL-6 and IL-13 in Donor 3. Crisaborole, known to reduce cytokine stimulation was used as an internal control in this study and again the extent of the reduction varied between donors. In many cases where the cytokine secretion was induced by Dynabeads, Crisaborole reduced the amount with one exception of IL-8 where there was no reduction in any donor (Tables 6-8). When Compound 8 was added to the PBMCs stimulated with Pam3CSK4, there was a significant reduction in multiple cytokines and again this varied between donors. Once again, there was a trend whereby if Pam3CSK4 induced cytokine secretion in a given donor, Compound 8 at 10 µM reduced this induction in almost all cases. Interestingly, Compound 8 at 1 µM in Pam3CSK4 stimulated PBMCs had a significant effect, reducing cytokine levels in almost all cases. Although in Donor 3, where there was no statistically significant increase in cytokines with the exception of IL-10 in response to Pan3CSK4 alone, both Compound 8 at 10 and 1 µM significantly reduced IL-2, IL-6, IL-8, IL-10 and TNFα in Pam3CSK stimulated PBMCs (Tables 6-8). Crisaborole in the Pam3CSK4 stimulated PBMCs reduced IL-10 and TNFα in all three donors and additionally GM-CSF, IL-1β, IL-17A and IL-23 in Donor 1. The data for Donor 1 is shown in FIGS.28A-28X. 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I 1 . 1 . 1 1 . 8 . 9 . ± 3 3 . . 1 ± ± 6 9 5 1 . g a e t 3 6 1 . 2 5 . 2 . . 5 0 0 6 0 4 7 9 3 . 9 2 . . 9 7 a 2 6 1 1 2 1 2 1 4 5 1 6 8 7 8 2 1 0 4 n l o i t u a m l its- $ 6 . 1 5 0 5 . 9 . 6 . 5 u 8 1 . 1 . $ . 8$ m 24 i n 1 2 u . 4 . 3 . t s t γ . N0 > R 1 > 1 0 ± R 1 . ± ± 3 1 . 8 . 2 1 ± 2 5- 03 . ± ± 0 ± 0 0 0 0 0 0 0 1 s ± ± ± ± hti n i F I ± 1 . O4 0 O. O0 3 2 ± . 8 . 7 . 0 1 7 . ± L I 1 . 1 . ± 1 3 . 0 1 . 1 . ± ± ± ± 2 a . 0 0 4 . 3 . wg a 0 O 2 0 6 2 7 1 0 1 4 5 5 . 1 3 4 5 0 0 2 0 0 1 t n e n mo t i a t a 9 5 e l u 2 7 † † rt mi F S * . * 0 6 . 3 . 4 * * * * * *†2. * * * * 3 . * * 4 2 * * 6 . 8 C < 3 5 7 0 4 2 . 2 . 3 . 9 . 2 . g n t i s g - R ± 1 ± < 4 . 0 2 . 0 1 < * * 7 . 0 3 6 ± 4- . 0 ± 4 . 3 4 ± ± . 0 0 0 0 0 1 r ± 2 . a ni MO2 . ± G O9 6 5 . R O± ± ± 3 . 1 8 7 R 3 O. 0 ± 5 . L I ± 3 . ± 5 . 4 . ± 3 . 1 ± ± ± ± p 3 r . 7 . 5 . 8 ma p 1 0 7 3 O. 6 . . 7 O 8 . 0 5 5 . 0 3 7 4 . 8 5 0 1 1 0 0 1 . 1 o c (
Figure imgf000260_0001
1 1 o c r o 0 n 0 0 . 0 o D ( O 0 0 0 s M M M S O S < . 0 M M M M $ p < C D µ MM µ MM µ M D D µ MM µ MM µ MM D ; 1 p M I e l 0 µ 1 1 µ 0 e 0 µ 1 1 µ 0 e n 0 µ 1 1 _ l I e l 0 µ 1 1 µ 0 e 0 µ 1 1 µ 0 e 0 µ 1 1 _ l 0 0 ; 1 B P p _ 8 _ 8 1 _ n o _ 8 _ 8 1 _ o _ 8 _ 8 o rt p _ 8 _ 8 1 _ n o _ 8 _ 8 1 _ n o _ 8 _ 8 o rt 0 . 0 0 n m i a d n d e n l l o a t d n d e l l a t d d n o ma d d e l l a t d d e l l a t d d n o 0 < 0 . 0 st S l u u r o n a u n u o r o n a n u n u c t d r S n u n u o r n a n u n u o r n a n u n u c t d r p * < u o p o p b l u o p o p b l u o p o p n e a d o p o p o b l u o p o p o b l u o p o p n e a d * *† p s e m R o ma o si r m i mo ma o si m i mmv l n a mma si m i mma si m i mmv l n a ; 1 † † ; e C C C t S C C r C t S o C o C o S t S o C o C r C t S o C o C r C t S o C o C o S t S 0 1 n 0 i . 0 0 k o t t d y n C a l s d s d s d s d 4 K4 K4 K4 e t d K a e l t d a e t d a e t a t d 4 4 4 4 e t d e t d e t d e 0 t < . p 0 * < p 2 . u a u l u l u l u n a l s d s d s d s d KKKK a l a l a l a l * † † . 3 0 7 e m e a e a e a e S l i t b a b a b a b a C S 3 C S 3 C S 3 C 3 mit mit mit mi u a t m e a e a e a e S i b a b a b a b a C S 3 C S S u u u u 3 C 3 C 3 mit mit mit mi ; t 1 ; 0 . 1 9 0 1 0 9 b a S n y n y n y n s y mmmm- s n - s n - s n -n t S n n n n mmmms- s- s- s- 0 . 0 7 4 1 T D D D Da P a P a P a P U U U U y Dy Dy Dy Da P a P a P a P n Un Un Un U< p < * / † p 1 B D OOR > Out of Range Above the Standard Curve (Logistic Regression) OOR < Out of Range Below the Standard Curve (Logistic Regression) Underlined Data single data point as other points are OOR Bold Data average of two data points as the third point is OOR Table 7 continued. Cytokine Results in PBMCs (Donor 1) Stimulant Sample ID IL-10 IL-12p70 IL-13 Dynabeads Compound 8_10 µM 0.1 ± 0* OOR <* OOR <$ 1196.4 ± Dynabeads Compound 8_1 µM 432.9 6.4 ± 5.3 557.5 ± 96.3* Dynabeads Crisaborole_10 µM 614.7 ± 56.3 0.2 ± 0* 214 ± 44.3*** Dynabeads Stimulant alone 2297 ± 859.3† 15.8 ± 3.6† 932.3 ± 33.3 Pam3CSK4 Compound 8_10 µM 0.5 ± 0.3** OOR < OOR < Pam3CSK4 Compound 8_1 µM 10.9 ± 5.5** OOR < 0.9 ± 0.5* Pam3CSK4 Crisaborole_10 µM 38.1 ± 11.2* 0.1 0.5 ± 0.6* Pam3CSK4 Stimulant alone 143 ± 24.6 1.9 ± 0.4 3.3 ± 0.2 Un-stimulated Compound 8_10 µM 0.1** OOR < OOR < Un-stimulated Compound 8_1 µM 0.7 ± 0.8 OOR < OOR < Un-stimulated Solvent control_DMSO 8.1 ± 3.5 OOR < 4.8 ± 3.6 Un-stimulated Standard 20.1 ± 11.1†† OOR < 10.8 ± 7.7 Stimulant Sample ID IL-17A IL-23 TNFα Dynabeads Compound 8_10 µM 0.2** 8.1 0.4 ± 0.1$ Dynabeads Compound 8_1 µM 176.3 ± 33.7* 10 ± 3.4 1608 ± 174.5* Dynabeads Crisaborole_10 µM 238 ± 28.5* 23.7 ± 6.7 117.4 ± 6.3$ Dynabeads Stimulant alone 523.2 ± 67.6†† 14.6 ± 4.5 2121.9 ± 35.7 Pam3CSK4 Compound 8_10 µM 0.1 ± 0.1* 4.8 ± 1.1* 4.6 ± 1.5$ Pam3CSK4 Compound 8_1 µM 0.3 ± 0.1* 6.1 ± 1.9* 21.9 ± 3.5*** Pam3CSK4 Crisaborole_10 µM 0.6 ± 0.3* 12 ± 3.9* 40.8 ± 3.8*** Pam3CSK4 Stimulant alone 11.2 ± 3.2 166.2 ± 34.9 719.1 ± 69.3 Un-stimulated Compound 8_10 µM 0.2 8.7 ± 3 4.9 ± 7.5* Un-stimulated Compound 8_1 µM 5.0 4.2 ± 3.9 13.4 ± 7.6 Un-stimulated Solvent control_DMSO 1.2 5.5 ± 2.2 39 ± 9.1 Un-stimulated Standard 8.9 ± 6.3 6.8 ± 2.2 118.3 ± 11.9 *p< 0.01; **p<0.001; ***p< 0.0001; $p< 0.00001 (comparing treatment with stimulation against stimulation alone) †p< 0.01; ††p<0.001; †††p< 0.0001; p< 0.00001 (comparing stimulation against un-stimulated conditions) OOR > Out of Range Above the Standard Curve (Logistic Regression) OOR < Out of Range Below the Standard Curve (Logistic Regression) Underlined Data single data point as other points are OOR Bold Data average of two data points as the third point is OOR DB1/ 147901903.2 260 0 5 O W-2 1 0 5-4 6 3 0 3 1 ** 3 2 * . 1 * † † 2 $ * * 7 . $ 3 7 . $ 67. 7 . 5 3 . 9 . - 2 . 6 7 . 2 3 0 1 1 . 1 . . 0 9 . 1 . 3 . 7 . 6 . * 1 3 0 1 . 9 6 0 2 1 0 8 . 4 . 4 8 L I 0 ± 1 0 0 ± ± 8 . ± 7 ± 2 ± 1 5 0 0 1 ± 5 3 ± . 8- 3 ± 2 5 1 ± 1 ± 1 6 7 ± ± 1 ± 1 7 ± 2 3 ± 1 2 L I 1 ± 4 1 1 3 . . ± 1 . 5 . 8 . ± 4 2 . 4 . ± 0 ± 3 ± 6 6 7 3 . 2 0 0 5 . . 4 7 4 . 9 1 0 . 0 . 1 . 7 . 0 . 0 . 2 4 5 1 1 3 1 1 1 9 0 8 1 . 6 6 4 1 3 1 . 7 . 3 2 8 3 1 0 4 1 0 5 9 3 4 4 7 2 1 2 4 . 2 . 1 5 6 . 2 . 4 6 1 1 . 2 . 7 * β . 1 - 0 . 1 1 L ± ± 1 4 2 . I 1 ± ± 0 . 0 7 6 ± ± ± 5 0 . ± ± 0 . 1 . 0 5 6 6 . 3 * 2 6 . ± 7 ±† 1 . 1 . 0 4 . 3 ± ± 1 . 6 . 9 . 1 . 7 . 2 4 4 . 8 . 1 . 3 . 9 0 - L I ± ± ± 3 . 1 3 2 4 . 8 ± 2 . . ± ± 9 8 . 8 41 0 . 0 1 ± ± ± 5 . . 4 5 3 0 8 2 1 2 . 5 . 0 0 2 2 . 2 6 3 0 . 0 4 1 3 0 7 0 . 1 . 0 4 1 7 2 8 4 8 1 . 4 1 7 9 2 0 0 5 † . 6 . † 8 γ 0 ± N 8 . 2 . 1 1 0 4 . F ± 1 0 . 7 0 . 2 < 1 4 2 5 * 4 1 * * . 2 2 I 1 . 0 6 1 ± 9 . 3 0 0 1 0 5 7 0 . 0 . 0 ± ± . 0 R 0 . 0 0 0 0 O. 0 3 . - L * 1 . ± 1 ± ± . 0 ± 1 ± ± ± ± 0 . 0 1 2 1 9 . 0 4 3 . 2 . O 0 I 0 9 . ± 8 0 . 2 0 0 0 2 0 3 2 2 1 4 . 6 0 . 7 0 1 1 6 2 FS * 1 *† 86. C < 1 < < 5 . 5 . * < < < * 3 . * † 1 †56 . 2 . 2 . 6 . 1 . 4 . - R ± . 1 1 R R 1 3 ± ± R R R 0 7 4 - 2 . 0 4 . 3 1 ± 0 0 0 0 0 0 ± ± ± 2 . 4 . MO 1 . 6 ± 1 ± 5 OO1 . 4 . OOO. 0 L I ± ± 4 ± ± 7 3 . 5 . 3 . 2 . 8 . 0 ± 4 ± 4 0 G O 2 . 4 . 8 O O 4 1 5 O O O 2 . 0 7 . 8 0 8 0 0 0 0 . 0 . 0 ) 2r o n o O O D ( S S s M C D I µ MM M 0 µ µ µ M µ M M µ µ MM M µ D D I µ M µ M M µ µ M µ M M µ µ MM µ D M e B l 1 P p _ 1 8 _ 0 e 8 1 _ n 0 o 1 l _ 1 0 e 8 _ 8 1 _ n 0 o 1 1 _ l 0 l _ 8 _ 8 or e t l 1 1 0 e p _ 8 _ 8 1 _ n 0 o 1 1 0 e n 0 1 1 _ l l _ 8 _ 8 1 _ o l _ 8 _ 8 ort n m i a d s S n d e u n l u o a r t n d d e l t a n u n u o a r t n d n d n o m u n u c t d r a d d e l S n u n u o a r t n d n d e l u n u o a r t n d n d n o u n u c t d r l o u p o p o b l o p o p o b a l o p o p n a o p o p o b a l o p o p o b a l o o n a se m mas u i mmmas u e i mmmv l d n mmas u mmm as u mp p mme v l d n R o C o C r i C t S o C o C r i C t S o C o C o a S t S o C o i C r i C t S o C o i C r i C t S o C o C o a S t S e n i k o t t d e y n t d e t d e t d e t t d e d e d e d e C a l s s s s 4 4 4 4 a . u d a d a d a d a K S K S K S K S l a u l a u l a u l n u a l s s s s 4 4 4 4 t a u d a d a d a d a KK K Kl t a u l t a u l t a u l 2 u . 3 0 8 e m i e l t b e e e a b a b a b a C 3 C 3 C 3 C 3 mit m s it m s it m s its m i e e e e S t b a b a b a b a C S 3 C S 3 C S 3 C 3 mit m s it m s it m s i 9 t 1 0 9 b S n a y n y n y n y mmmm-n -n -n -n S n y n y n y n mm m m- - - s - 7 4 1 T D D D Da P a P a P a P U U U U D D Dy Da P a P a P a P n Un Un Un U / 1 B D *p< 0.01; **p<0.001; ***p< 0.0001; $p< 0.00001 (comparing treatment with stimulation against stimulation alone) †p< 0.01; ††p<0.001; †††p< 0.0001; p< 0.00001 (comparing stimulation against un-stimulated conditions) OOR > Out of Range Above the Standard Curve (Logistic Regression) OOR < Out of Range Below the Standard Curve (Logistic Regression) Underlined Data single data point as other points are OOR Bold Data average of two data points as the third point is OOR Table 8 continued. Cytokine Results in PBMCs (Donor 2) Stimulant Sample ID IL-10 IL-12p70 IL-13 Dynabeads Compound 8_10 µM OOR < OOR < OOR < Dynabeads Compound 8_1 µM 524.6 ± 172.6 10.4 ± 5.7 266.1 ± 13** Dynabeads Crisaborole_10 µM 91.8 ± 15.6 OOR < 29.4 ± 7.9$ Dynabeads Stimulant alone 680.4 ± 280 2.9 ± 2 439.5 ± 12.3 Pam3CSK4 Compound 8_10 µM 0.2 OOR < OOR < Pam3CSK4 Compound 8_1 µM 2.3 ± 1*** OOR < OOR < Pam3CSK4 Crisaborole_10 µM 12.7 ± 4** 0.0 1.4 ± 1.4 Pam3CSK4 Stimulant alone 61.9 ± 6.4††† 0.0 5.7 ± 4 Un-stimulated Compound 8_10 µM 0.0 OOR < OOR < Un-stimulated Compound 8_1 µM 0.06 OOR < OOR < Un-stimulated Solvent control_DMSO 3.1 ± 1.5 OOR < OOR < Un-stimulated Standard 3.4 OOR < 0.48 Stimulant Sample ID IL-17A IL-23 TNFα Dynabeads Compound 8_10 µM 0.3 2.3 0.3 ± 0.1* Dynabeads Compound 8_1 µM 22 ± 4.1 5.5 ± 2.2 280.9 ± 35.6 Dynabeads Crisaborole_10 µM 33.8 ± 14.6 7.4 ± 4 31.5 ± 8.1 Dynabeads Stimulant alone 89.8 ± 50.1 8.1 ± 3.9 548.6 ± 205.3† Pam3CSK4 Compound 8_10 µM 0.1 2.9 ± 4.5 2.3 ± 0.2** Pam3CSK4 Compound 8_1 µM 1.4 4.2 ± 3.9 11 ± 0.2** Pam3CSK4 Crisaborole_10 µM 1.5 ± 1.4 5.5 ± 2.2 30.2 ± 6.8** Pam3CSK4 Stimulant alone 3.1 ± 2.3 8.1 ± 0 312.9 ± 41.9†† Un-stimulated Compound 8_10 µM OOR < 6.8 ± 2.2 0.2 ± 0.1 Un-stimulated Compound 8_1 µM 0.2 4.2 ± 3.9 0.4 ± 0.1 Un-stimulated Solvent control_DMSO 1.2 4.2 ± 3.9 7.3 ± 5.3 Un-stimulated Standard 0.89 8.1 2.0 *p< 0.01; **p<0.001; ***p< 0.0001; $p< 0.00001 (comparing treatment with stimulation against stimulation alone) †p< 0.01; ††p<0.001; †††p< 0.0001; p< 0.00001 (comparing stimulation against un-stimulated conditions) DB1/ 147901903.2 262 OOR > Out of Range Above the Standard Curve (Logistic Regression) OOR < Out of Range Below the Standard Curve (Logistic Regression) Underlined Data single data point as other points are OOR Bold Data average of two data points as the third point is OOR DB1/ 147901903.2 263 0 5 O W-2 1 0 5-4 6 3 * 5 . 0 * 5 1 † . † 2 . 2 3 9 3 1 2- . 5 6 6 . 2 8 * * $63 . 4 1 . 8 . 0 . 4 9 1 . 9 . 9 1 3 9 1 . 1 . 6 . 6 1 . 1 * 0 * 8 3 . 2 0 . . 0 4 4 4 5 2 * 7 * 1 9 1 7 8 . 2 5 6 L 7 I ± ± ± 1 ± 0 0 ± ± ± ± ± . 0 2 ± ± 8- 1 ± ± ± . . 1 1 9 4 ± 1 2 ± ± ± . 4 ± 4 ± ) e 3 1 . . 4 . 4 . 2 2 5 . 5 . 2 . ± 5 . 2 . L I 6 . 6 . . 0 6 . ± ± 3 . 3 . 8 . 1 4 . 5 . n o 5 9 4 4 2 5 7 . 0 . 0 4 4 0 1 1 4 6 8 7 5 6 1 8 3 3 4 l 3 6 4 1 4 5 4 4 2 4 6 8 4 0 2 3 5 a 1 2 1 3 4 2 6 n o i t a l ) u s n o † m i i t i * 5 . * † 8 * 2 . 8 . † 3 . * * 8 7 . t s t d n β1 1 . 6 7 . . - 0 8 4 0 0 . 9 0 . 3 1 . 1 0 . 3 * 3 2 3 7 7 1 . 2 . . 4 3 1 0 7 . 0 6 . 1 . s n o c L I ± ± 5 3 ± ± ± 1 1 4 . . ± 8 . 0 1 . ± ± . 1 0 . 6 0 ± ± - 0 0 6 . 6 . 6 . 4 . L I ± ± 1 1 0 0 1 . 3 . ± ± ± ± ± ± ± 3 2 1 ± ± ± i a d e 5 0 2 . 1 2 7 . 9 . . 0 5 . 1 . 4 . g a t a 0 3 1 6 7 6 2 0 2 0 2 0 0 1 4 5 7 . 1 0 . 0 6 1 6 0 4 4 n l 1 3 o i t u a m l it u s- † m n 3 u γ > 6 6 > < 2 . * 0 < < * 7 5 1 . . * † 6 * † i t 5 4 . . s t 2 0 0 0 0 0 0 0 h s ti n i a N* F 5 I . R ± 0 O3 R 1 . 0 R 2 . 0 ± R R 1 . 4 0 . 0 - L 0 5 6 1 ± ± ± ± 0 ± ± 1 ± 1 . 0 1 ± w t g a O. 2 O O 1 O O 2 . OO I ± ± ± 5 0 O O 1 . 0 3 9 9 . 7 4 . 0 . 1 0 0 . 0 . 0 0 1 . 0 n e n o 2 mi 4 1 t a t a 6 e l u 2 rt g mit FS * 6 . 1 8 . † 6 †9. 2 < < < < < < 2 . *† 89 . . 1 2 . 4 . 3 . 2 . 2 . 3 n . i s r a g n C- * 8 2 1 . ± 1 ± ± R R R 1 . 0 4 0 R - * 8 2 1 3 0 0 0 0 0 4 0 p ir OR OR O3 . 4 0 L I . 1 ± . 6 ± ± ± ± ± ± . ± a 7 ± 0 2 4 4 . 2 2 0 m G 9 O O
Figure imgf000265_0001
O O O 4 . 9 . 3 0 . 0 0 . 0 . 0 c ( o 3 0 r 0 1 o 0 n 0 0 o . 0 D O 0 0 ( S O S < 0 . 0 s MMM MMM MMM MMM MMM MMM $ p < C D µ µ µ µ µ µ µ µ D D µ µ µ µ µ µ µ µ D ; 1 p M I B e 0 l 1 1 0 e P p _ 8 _ 8 1 _ n 0 o 1 1 0 e n 0 1 1 _ l I 0 l _ 8 _ 8 1 _ o l _ 8 _ 8 or e t l 1 1 0 e p _ 8 _ 8 1 _ n 0 o 1 _ 1 0 e 8 _ 8 1 _ n 0 o 1 _ 1 _ l 8 _ 8 o 0 rt 0 ; 0 . 1 0 n m i a d d e l st S n u n u o a r t n d n d e l u n u o a r t n d d n o m l o a n u n u c t d r a d d e l l S n u n u o a r t n d n d e l l a u n u o r t n d n d n o 0 0 0 u n u c . t d r < p 0 u s p o p o b a l o p o p o b l o p o p n a o p o p o b a l o p o p o b a l o p o p n a * < mmas u i mmmas u e i mmmv l d n mmas u i mmmas u mmme v l d n * *† †p e R o C o C r i C t S o C o C r i C t S o C o a C o t o o r i t o o i r i t o o o a t ; 1 † ; e S S C C C S C C C S C C S S 0 1 n i 0 . 0 k 0 . o t t d e d e d e d e t d e d e d e d e 0 < 0 y n < C a l s s s s 4 4 4 4 t a . u d a d a d a d a K S K S KKl t a u l t a u l t a u l n u a l s s s s 4 4 4 4 t a t a t a t a p * u d a d a d a d a KKKKl u l u l u l u * ; † † p 2 . 3 0 9 e m i e e e e l t b a b a b a b a C 3 C S 3 C S 3 C 3 mit m s it m s it m s its m i e e e e S t b a b a b a b a C S 3 C S 3 C S 3 C 3 mit m s it m s it mit 1 ; 0 . 1 9 0 1 . 0 9 b S n a y n y n y n y mmmm-n -n -n -n S n y n y n y n y mmmm-n - s- s- 0 0 7 4 1 T D D D Da P a P a P a P U U U U D D D Da P a P a P a P Un Un Un U< p < * / † p 1 B D OOR > Out of Range Above the Standard Curve (Logistic Regression) OOR < Out of Range Below the Standard Curve (Logistic Regression) Underlined Data single data point as other points are OOR Bold Data average of two data points as the third point is OOR Table 9 continued. Cytokine Results in PBMCs (Donor 3) Stimulant Sample ID IL-10 IL-12p70 IL-13 Dynabeads Compound 8_10 µM 1.1 ± 1.7* OOR < 2.1$ Dynabeads Compound 8_1 µM 924.3 ± 113.9 8.1 ± 4.3 640.6 ± 96.1 Dynabeads Crisaborole_10 µM 202.5 ± 76.1 0.3 334.9 ± 135.7* Dynabeads Stimulant alone 736.6 ± 222.4† 7.4 ± 3.8 750 ± 41.9 Pam3CSK4 Compound 8_10 µM 0.0* OOR < OOR < Pam3CSK4 Compound 8_1 µM 0.1* OOR < OOR < Pam3CSK4 Crisaborole_10 µM 1.2 ± 0.2* OOR < 1.9 ± 0.7 Pam3CSK4 Stimulant alone 5.9 ± 1.7† OOR < 0.4 ± 0.4 Un-stimulated Compound 8_10 µM 0.1 OOR < OOR < Un-stimulated Compound 8_1 µM 0.1 OOR < 0.1 Un-stimulated Solvent control_DMSO 1.4 ± 0.3 0.2 0.4 ± 0.3 Un-stimulated Standard 3.2 ± 1.3 OOR < 3.4 ± 2.2 Stimulant Sample ID IL-17A IL-23 TNFα Dynabeads Compound 8_10 µM 4.4* 8.1 ± 3.9 1.6 ± 1.8*** Dynabeads Compound 8_1 µM 79.2 ± 22 7.4 ± 1.1 1410.4 ± 93 Dynabeads Crisaborole_10 µM 61.1 ± 7.7 10.7 ± 5.9 61.8 ± 33.5*** Dynabeads Stimulant alone 113.5 ± 31.9* 48.3 ± 25.3 1417.6 ± 94.7 Pam3CSK4 Compound 8_10 µM 0.1 4.2 ± 3.9 0.2 ± 0** Pam3CSK4 Compound 8_1 µM OOR < 0.3 ± 0* 0.5 ± 0.1** Pam3CSK4 Crisaborole_10 µM 0.3 ± 0.1 4.2 ± 3.9 1.6 ± 0.3** Pam3CSK4 Stimulant alone 1.2 ± 1 10.7 ± 2.2 25 ± 4.2 Un-stimulated Compound 8_10 µM OOR < 1.6 ± 2.2 0.2 ± 0.1* Un-stimulated Compound 8_1 µM OOR < 4.2 1.1 ± 1 Un-stimulated Solvent control_DMSO 0.2 8.1 15.9 ± 3.6 Un-stimulated Standard 0.2 5.5 ± 2.2 18.9 ± 10.9 *p< 0.01; **p<0.001; ***p< 0.0001; $p< 0.00001 (comparing treatment with stimulation against stimulation alone) †p< 0.01; ††p<0.001; †††p< 0.0001; p< 0.00001 (comparing stimulation against un-stimulated conditions) OOR > Out of Range Above the Standard Curve (Logistic Regression) OOR < Out of Range Below the Standard Curve (Logistic Regression) Underlined Data single data point as other points are OOR Bold Data average of two data points as the third point is OOR DB1/ 147901903.2 265 Table 10. Cell Viability Post-Treatment Donor Viable ID Stimulant Sample ID Viable % Parent Events/μL(V) Donor 1 Dynabeads Compound 8_10 µM 95% ± 1% 544 ± 22 Dynabeads Compound 8_1 µM 94% ± 0% 658 ± 34 Dynabeads Crisaborole_10 µM 96% ± 0% 646 ± 4 Dynabeads Stimulant alone 91% ± 0% 585 ± 16 Pam3CSK4 Compound 8_10 µM 96% ± 0% 562 ± 16 Pam3CSK4 Compound 8_1 µM 98% ± 0% 649 ± 28 Pam3CSK4 Crisaborole_10 µM 98% ± 0% 724 ± 34 Pam3CSK4 Stimulant alone 99% ± 0% 707 ± 15 Un-stimulated Compound 8_10 µM 96% ± 1% 586 ± 35 Un-stimulated Compound 8_1 µM 96% ± 1% 700 ± 32 Un-stimulated Solvent control_DMSO 99% ± 0% 683 ± 26 Un-stimulated Standard 99% ± 0% 732 ± 48 Donor 2 Dynabeads Compound 8_10 µM 92% ± 0% 331 ± 28 Dynabeads Compound 8_1 µM 96% ± 1% 490 ± 11 Dynabeads Crisaborole_10 µM 96% ± 0% 463 ± 5 Dynabeads Stimulant alone 95% ± 1% 425 ± 18 Pam3CSK4 Compound 8_10 µM 94% ± 0% 342 ± 22 Pam3CSK4 Compound 8_1 µM 95% ± 1% 422 ± 13 Pam3CSK4 Crisaborole_10 µM 97% ± 0% 469 ± 6 Pam3CSK4 Stimulant alone 98% ± 0% 494 ± 22 Un-stimulated Compound 8_10 µM 93% ± 0% 347 ± 11 Un-stimulated Compound 8_1 µM 92% ± 1% 391 ± 33 Un-stimulated Solvent control_DMSO 98% ± 1% 400 ± 5 Un-stimulated Standard 98% ± 0% 410 ± 58 Donor 3 Dynabeads Compound 8_10 µM 94% ± 2% 556 ± 81 Dynabeads Compound 8_1 µM 94% ± 1% 647 ± 21 Dynabeads Crisaborole_10 µM 97% ± 0% 676 ± 23 Dynabeads Stimulant alone 94% ± 0% 651 ± 31 Pam3CSK4 Compound 8_10 µM 94% ± 1% 545 ± 59 Pam3CSK4 Compound 8_1 µM 95% ± 0% 601 ± 13 Pam3CSK4 Crisaborole_10 µM 97% ± 0% 663 ± 13 Pam3CSK4 Stimulant alone 98% ± 0% 683 ± 60 Un-stimulated Compound 8_10 µM 94% ± 1% 567 ± 39 Un-stimulated Compound 8_1 µM 96% ± 0% 601 ± 5 Un-stimulated Solvent control_DMSO 98% ± 0% 678 ± 48 Un-stimulated Standard 98% ± 0% 714 ± 64 Conclusions This experiment assessed the effect of Compound 8 on cytokine secretion in PBMCs from three normal donors, which were pre-treated with CD3-CD28 Dynabeads or Pam3CSK4. DB1/ 147901903.2 266 Treatment with Dynabeads or Pam3CSK4 induced a number of cytokines in all donors, though Donor 3 had much less induction in response to Pam3CSK4. When Compound 8 was added to the PBMCs stimulated with Dynabeads, there was a significant reduction in multiple cytokines and again this varied between donors. However, there was a trend whereby if the Dynabeads induced cytokine secretion in a given donor, Compound 8 at 10 µM reduced this induction in almost all cases. Compound 8 at 1 µM had less impact. In many cases where the cytokine secretion was induced by Dynabeads, Crisaborole reduced the amount with one exception of IL- 8 where there was no reduction in any donor. When Compound 8 was added to the PBMCs stimulated with Pam3CSK4, there was a significant reduction in multiple cytokines and again this varied between donors. Once again, there was a trend whereby if Pam3CSK4 induced cytokine secretion in a given donor, Compound 8 at 10 µM reduced this induction in almost all cases. Interestingly, Compound 8 at 1 µM in Pam3CSK4 stimulated PBMCs also had a significant effect, reducing cytokine levels in almost all cases. Crisaborole in the Pam3CSK4 stimulated PBMCs reduced IL-10 and TNFα in all three donors and additionally GM-CSF, IL- 1β, IL-17A and IL-23 in Donor 1. Cell viability was never compromised in any of the treatment conditions, therefore changes in cytokine levels are due to compound activity and not cell death. Reference Römer, Paula S. et al., “Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412,” Blood, 2011, Vol.18, No.2 Example 4. In Vitro Evaluation of Compound 8 on Cytokine Secretion in PBMCs from Three Normal Human Donors Pre-treated with Dynabeads or Pam3CSK4 Summary This experiment assessed the effect of Compound 8 on cytokine secretion in PBMCs from three normal donors, which were pre-treated with CD3-CD28 Dynabeads (adaptive immune response stimulator) or Pam3CSK4 a TLR agonist stimulating innate immune responses. Treatment with Dynabeads or Pam3CSK4 induced a number of cytokines in all donors. Variation was seen between donors, but this was an expected finding (Romer et al, 2001). When Compound 8 was added to the PBMCs stimulated with Dynabeads, there was a significant reduction in multiple cytokines and this varied between donors. However, there was DB1/ 147901903.2 267 a trend whereby if the Dynabeads induced cytokine secretion in a given donor, Compound 8 at 10 µM reduced this induction in all cases and additionally at 3 and 1 µM for a limited range of cytokines (IL-1 β in two of three donors and IL-6 in all donors). Crisaborole reduced the amount with one exception of IL-8 where there was no reduction in any donor. When Compound 8 was added to the PBMCs stimulated with Pam3CSK4, there was a significant reduction in multiple cytokines and again this varied between donors. In some cases, where Pam3CSK4 alone did not induce a statistically significant induction as compared to the solvent control, co -culture of Pam3CSK4 and Compound 8 significantly reduced the cytokine induction. For Donor 1, Compound 8 reduced IL-8 and IL-10 from 10 – 0.3 µM and TNFα from 10 – 1 µM. For Donor 2, Compound 8 reduced IL-6 from 10 – 0.3 µM, IL-8 from 10 – 1 µM, IL-10 and TNFα from 10 – 0.1 µM. For Donor 3, Compound 8 reduced IL-6 and TNFα from 10 – 0.1 µM, IL-8 and IL-10 from 10 – 0.3 µM and IL-17 at 10 µM. Cell viability was never compromised in any of the treatment conditions, therefore changes in cytokine levels are due to compound activity and not cell death. There was no consistent trend in cytokine inhibition across donors with either stimulation below 1 µM Compound 8. Terminology and Definitions rh: recombinant human TNF-α: Tumor Necrosis Factor-alpha IL-1 β: Interleukin 1 beta IL-2: Interleukin 2 IL-4: Interleukin 4 IL-5 : Interleukin 5 IL-6: Interleukin 6 IL-10 : Interleukin 10 IL-12 : Interleukin 12 IL-13 : Interleukin 13 IL-17: interleukin 17 IL-23: interleukin 23 GM-CSF : Granulocyte macrophage colony stimulating factor IFN-γ: Interferon gamma PBMC: peripheral blood mononuclear cells DB1/ 147901903.2 268 PBS: phosphate buffered saline FBS: fetal bovine serum mins: minutes r.p.m. revolutions per minute HI: heat inactivated OOR: out of range IRB: Institutional Review Board Table 11. Reagent List Reagent Vendor Cat. No. Lot no. Lymphoprep StemCell Technologies 07851/07861 00322 RPMI Gibco 21870-076 2492873 FBS Peak Serum PS-FBI 01J1211 Crisaborole Selleckchem S5014 S501401 Dynabeads (CD3/CD28) Gibco 11131D 01266483 Pam3CSKR4 InvivoGen tlrl-pms 5930-44-05 PBS Gibco 14190-144 2662076 DAPI Biolegend 422801 B358421 GlutaMax Gibco 35050-061 2323163 150 mL filter unit Thermo Scientific 565-0020 1384482 96 well round bottom, non-treated Corning 3788 21422013 96-well round bottom, polypropylene USA Scientific 1830-9610 J190390L-2129 0.6 mL microtube Corning MCT-060-C 07020017 Table 12. Donor Information Age Race Blood Type Other Notes 1 38 Caucasian O negative CMV positive 2 29 Caucasian AB Positive CMV negative 3 72 Caucasian O Positive CMV negative Purpose The aim of the study was to evaluate cytokine secretion in response to Compound 8 and controls in PBMCs derived from three normal human donors. DB1/ 147901903.2 269 Tests Performed Cytokine secretion (TNFα, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFNƴ) was evaluated in response to Compound 8 and controls in PBMC. Preparation of PBMCs Fresh blood was acquired from Bloodworks within 4 hours of collection. The donors were fully consented, and the blood was collected under IRB. The fresh blood samples were diluted with an equal volume of PBS + 2% FBS and layered over ficoll (Lymphoprep). The tubes were placed in the centrifuge at a speed of 1200 r.p.m. with the brake set to the “off” position. PBMCs were harvested from the buffy layer and transferred to a new tube and washed with PBS + 2% FBS. The cells were then resuspended in RPMI + 10% HI-FBS, the cells were counted manually using glacial acetic acid and a Neubauer hemacytometer and then, to each well of a 96-well plate, 200,000 cells were added. Test Articles and Controls Compound 8 was provided in solution (10 mM). For the PBMC assay, working stocks were made in RPMI + 10% HI-FBS to generate concentrations of 200, 60, 20, 6, 2, 0.6, 0.2 and 0.06 µM. Additionally working stocks of Crisaborole were prepared at 200 µM. When added in at 1: 20 v/v, the desired test concentrations of Compound 8 were 10, 3, 1, 0.3, 0.1, 0.03, 0.01 and 0.003 µM and for Crisaborole was 10 µM. Method Summary PBMC Assay Format Fresh human blood was obtained from 3 normal donors and PBMCs were prepared as described above. Once the cells had been prepared, three cell stocks were generated for Dynabeads-stimulated, Pam3CSK4-stimulated and unstimulated controls. For Dynabeads treated cells, a cell stock at 1.06 x 10^6/mL was mixed with equal volume of Dynabeads resuspended in RPMI + 10% HI-FBS (1:1 cells to beads ratio) and then 190 µL were added wells of a 96-well plate (100,000 cells/well). Similarly, for Pam3CSK4 treated cells, a cell stock at 1.06 x 10^6/mL was mixed with equal volume of Pam3CSK4 at 20 ng/mL in RPMI + 10% HI- FBS (Pam3CSK4 final concentration at 10 ng/mL) and then 190 µL were added wells (100,000 cells/well). For un-stimulated control cells, a cell stock at 0.53 x 10^6/mL was prepared and 190 µL were added to wells (100,000 cells/well). Test article Compound 8 and Crisaborole were prepared as described above, when 10 µL were added to 190 µL cells, the desired test DB1/ 147901903.2 270 concentrations were achieved. PBS was added to the exterior wells of the 96-well plate to retain a high and equal humidity. The content of cells and compounds were mixed and incubated at 37°C, 5% CO2 for 48 hours. After the 48-hour incubation, supernatants were harvested (170 µL) and divided between a well (95 µL) or an Eppendorf tube (75 µL). The supernatants in the wells were retained at -80oC for backups and the supernatants in the Eppendorf tubes were coded and sent to Eve Technologies for cytokine analyses using the Luminex platform. The cytokines evaluated included GM-CSF, IFNy, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL- 17A, IL-23 and TNFα. Following removal of the supernatants for cytokine analyses, the cells were resuspended in PBS containing 2% FBS and stained with DAPI for cell viability assessed by flow cytometer. Statistical Analyses of Data For each condition, triplicate tests were performed. Cytokine analyses were assessed using the Luminex platform. Where mean and standard deviations are reported, the values used to generate these numbers did not include values that were below the limits of quantitation. Where a value was OOO<, the value for the lower limit of detection for a given cytokine was used and where the value was OOO>, the upper limit of quantitation was used in order to get a significant value. In this analysis, the Dynabead, Pam3CSK4 or Compound 8 alone treated cultures were compared with unstimulated cultures whereas the Compound 8 cocultures with the Dynabeads or Pam3CSK4 were compared with Dynabeads or Pam3CSK4 alone cultures. Due to the potential subjectivity of cytokine release, a p value of less than 0.01 is deemed significant. Results The results of experiments to evaluate the potential effect of Compound 8 on secretion of cytokines in stimulated PBMC (Dynabeads or Pam3CSK4) and controls (Crisaborole) are presented in Tables 13-15 and cell viability data for each test article on each donor is presented in Tables 16-18. The viability data served to confirm that the PBMCs remained viable over the course of the experiment and therefore any changes in cytokine secretion is due solely to the activity of the test articles and not cell death. Pre-treatment of PBMCs with CD3-CD28 Dynabeads induced increases in multiple cytokines in all donors when compared to the unstimulated controls, but the extent of the increase and the actual cytokines varied between donors. Increases in GM-CSF, IL-1B, IL-2, IL- 4, IL-5, IL-10 and IL-17 were consistent among all three donors (Tables 13-15). Pam3CSK4 DB1/ 147901903.2 271 only induced IL-8 in Donor 1 (Table 13), IL-6 and IL-10 in Donor 2 (Table 14) and IL-8, IL-10, IL-17 and TNFa in Donor 3 (Table 15). Compound 8 did not induce any cytokines when compared to the unstimulated controls (Tables 13-15). When Compound 8 was added to the PBMCs stimulated with Dynabeads, there was a significant reduction in multiple cytokines and again this varied between donors. However, there was a trend whereby if the Dynabeads induced cytokine secretion in a given donor, Compound 8 at 10 µM reduced this induction in all cases and additionally at 3 and 1 µM for a limited range of cytokines (IL-1 β in two of three donors and IL-6 in all donors). Crisaborole, known to reduce cytokine stimulation, was used an internal control in this study and again the extent of the reduction varied between donors. In many cases where the cytokine secretion was induced by Dynabeads, Crisaborole reduced the amount with one exception of IL-8 where there was no reduction in any donor (Tables 13-15). When Compound 8 was added to the PBMCs stimulated with Pam3CSK4, there was a significant reduction in multiple cytokines and again this varied between donors. In some cases, where Pam3CSK4 alone did not induce a statistically significant induction as compared to the solvent control, co-culture of Pam3CSK4 and Compound 8 significantly reduced the cytokine induction. For Donor 1, Compound 8 reduced IL-8 and IL-10 from 10 – 0.3 µM and TNFα from 10 – 1 µM (Table 13). For Donor 2, Compound 8 reduced IL-6 from 10 – 0.3 µM, IL-8 from 10 – 1 µM, IL-10 and TNFα from 10 – 0.1 µM (Table 14). For Donor 3, Compound 8 reduced IL-6 and TNFα from 10 – 0.1 µM, IL-8 and IL-10 from 10 – 0.3 µM and IL-17 at 10 µM (Table 15). Crisaborole in the Pam3CSK4 stimulated PBMCs reduced TNFα in all three donors and additionally IL-10 in Donor 2. The data for Donor 1 is in FIGS.28A-28V. 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R OR 0 0 . R 0 0 4 2 . 0 . 0 . R 2 0 . s h s n i R R R 8 8 . 8 1 1 5 . 8 . 0 O 0 O 0 0 0 O 0 ti a c c 8 O O O O wg i ts i t O 42 1 2 2 2 1 2 2 t n a e n i g si O g s mo t i t o a L o i ( L ( t n i 5 7 . † a l u e e R o 2 7 1 5 . 1 0 5 . † e 3 5 3 * * 2 . rt mi v v O p t r u r u O dr ± ± ± 6 6 2 < R < R < R < R 9 9 9 < R < g R 9 ni s g C d C e r i h t 3 ± . 1 9 . 3 5 . 9 5 ± . 3 OOOO0 . 0 . O O O O 0 . 0 0 . 0 0 OO. r O O 0 a p ni r r a d r d a a d s t e h t 1 2 4 2 4 2 2 3 2 0 m 2 o a c p n a n a n i o s ( m a 1 o t S t 0 c ( e S pr s t n 0 0 1 h e h e h i 0 0 t e t t o o p . 0 0 0 v o w b o l s a t e at a M O M O < 0 . A n d M µ M µ µ S MMM µ M µ µ S $ p 0 B i o 30 . 1 3 0 . 0 0 MMMMM µ µ 3 MM; < e p g e n g o n p w a tf . µ D µ _ 0 µ µ 3 . 1 . 3 0 . 1 0 . 0 0 . µ D_ 1 0 ; a R a t a o 0 _ 0 8 _ 0 8 _ 0 l 8 1 or 1 t _ 3 8 _ 1 8 _ 0 8 _ 0 8 _ 0 _ 0 _ 0 _ 0 1 l o 0 rt 0 . 1 0 0 f R o f d e o e l g a d _ e n d u n d n l n 8 8 8 8 _ e n 0 0 o . t t g r e o u r o c d n d n d n d n d n d n d n d n l o o c < p 0 u Ou Oni v p o u p o p o b t n u o u o u o u o u o u o u o u o r o b t n * * < s a †p mo mmas e p p p p p p p p i v l mmmmmmmmas e i v l * ; † † ; C o C o C r C o S o C o C o C o C o C o C o C o C r C o S 1 0 0 . 1 0 0 < 0 . a 0 t a sd s a d s d s d s d 4 e a e a e a e a e K 4 4 4 4 4 4 4 4 4 p * < D S K S K S K S K S K S K S K S K S K S * ; † † p d e a 2 . 3 1 ; n i t a 0 9 b a b b b b C n a 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 0 . 1 0 > < l r e D 1 0 9 y n a y n a y n a y n y mmmmmmmmmm0 . 0 R OR Od n d l 7 o 4 1 D D D D D a P a P a P a P a P a P a P a P a P a P < p < * † p O O U B / 1 B D 0 5 O W-2 1 8 * . 2 . 8 . 7 . 7 . 1 . * 5 . 2 0 . 4 1 . 9 4 . 2 8 . 6 0 . 2 2 . 9 . † † 5 7 † 7 . 1 5 8 0 A 7 5 2 < R 0 1 0 2 1 0 1 0 1 0 1 * 4 . 6 1 1 2 3 3 2 1 ± ± ± ± ± ± ± 1 7 2 5 0 0 5 . 0 . 0 . 0 5- 1- . 0 O. 0 . 0 ± ± ± 6 6 5 1 . 0 ± ± ± 3 ± 2 1 6 6 7 3 9 1 1 9 3 ± . 0 0 . 0 1 . 0 6 . 1 ± ± ± 4 6 L 3 I O . 1 . 0 . 1 . 1 . 0 . 0 ± 8 . . . . . . . 1 . 0 . 3 4 4 4 7 6 4 8 0 1 9 3 . 4 7 . 0 7 . 0 2 . 1 3 4 1 2 2 1 3 4 3 3 3 6 3 2 5 8 2 1 * * 7 3 4 † 3 * 9 . 4 . 1 9 . 2 . . 9 . . 0 4 5 . 5 8 4 † † 1 7 1 < - R < R < R < R 0 L OOOO8 4 . 0 9 0 5 0 0 8 7 . 0 . 0 . 9 0 . 8 0 . 0 7 . 0 3 . 0 1 5 6 1 ± 1 9 2 8 0 6 ± ± 1 3 3 5 1 3 ± 5 < R < R < . R 5 9 9 0 5 ± 3 ± 9 ± ± ± 1 6 6 2 OOO. 0 0 . 0 0 . 0 ± I O O O O ± . 1. 5 3 . 4 8 6 . 6 9 . 7 1 3 6 5 7 . 7 . 1 1 . 0 O O O 5 . 1 0 9 5 0 8 7 7 2 8 4 1 7 0 * † 7p 1 . 0 0 0 1 . 0 1 . 1 . 0 0 0 * 4 4 . 2 0 4 9 . 4 3 . 1 2 . 0 6 . 3 8 7 . 4 * * † 4 2 . 1 . 0 0 0 1 . 1 - ± ± 1 ± 2 ± 0 ± ± 0 0 ± ± ± ± ± . 0 ± 2 3 3 3 ± ± ± ± 1 . 6 0 0 0 0 5 ± 1 ± 1 . ± ± ± ± 1 . ± L 1 I . 0 . 0 . 1 0 . 0 2 . 1 0 . 0 1 . 1 0 . 1 0 . 1 0 . 1 0 . 0 ± 4 8 . . ± 3 . 3 . 3 . . 6 9 . ± 1 . 0 1 . 1 . 1 . 1 . 0 1 . 0 7 3 2 6 1 7 5 5 2 7 5 1 5 9 . 3 9 4 0 0 0 0 0 6 * 5 ] 4 . 2 1 4 † † † 7 2 †57 . 2 7 5 8 1 * * 7 . . 1 8 9 5 7 9 . 4 8 . . 3 3 0 7 . * 2 7 5 5 * 9 7 . 4 . 0 * * ) 0 * * * 4 7 . 2 1 1 † 0 † 0 † 0 . 0 8 . 2 . 0 . 2 . 1 2 ± . 4 * 5 . 9 3 1 1 9 1 2 7 3 7 4 6 * * * * * 9 . . 1 2 . 2 r - L 9 . n 0 1 . 0 3 . ± ± ± ± ± ± 8 0 ± 3 . 8 9 . 8 ± ± ± ± 4 ± 1 ± ± 5 ± ± 4 0 < R 0 1 1 ± ± ± 8 ± o I 2 . o 1 1 1 . 4 9 . 5 5 . 9 5 . 6 9 . 9 ± 5 7 . . 7 . 9 . . 9 . 3 5 . . 9 5 . 3 . . 0 O. 0 3 8 . 6 . 0 4 1 6 4 3 3 9 5 0 3 0 0 2 1 3 8 4 2 0 0 O 1 D ( 4 s 2 8 6 1 7 7 7 2 8 9 3 6 0 6 C M B P n i MMM µ O S MMM µ O S MM st M MM µ MM µ µ µ 3 µ MM 1 3 0 MM MMM µ µ µ µ 3 MM MMMMM µ µ µ µ lu s D I e 0 µ µ 3 1 3 1 . 1 0 . 0 0 . 0 0 . 0 0 . 0 µ D µ _ l 0 µ µ 3 1 3 1 . 1 3 0 . 0 1 0 . 0 0 0 . 0 0 . 0 µ D µ 3 1 _ l 0 µ µ 3 1 3 1 . 1 . 0 . 0 . e l _ _ _ _ _ _ _ _ 0 o _ _ _ _ _ _ _ _ 0 o 0 0 0 0 R p 8 8 1 rt 8 8 8 8 8 8 8 8 1 rt _ _ _ _ _ _ _ e m i d d 8 d 8 d 8 d 8 8 8 _ e n _ e n 8 8 8 8 8 8 8 n a k S n n n n n d n d n d n l o o c d n d n d n d n d n d n d n d n l o o c d n d n d n d n d n d n d n o u t o u p o u p o u p o u p o u p o u p o u p o r p o b t d n r a u o u p o u p o u p o u p o u p o u o u o r o b t n u o u o u o u o u o u o u o y mmmmm a s e v d n p p p a s e v p p p p p p p C . o o o o o mo mo mo i r l o a t mo mo mo mo mo mo mo mo i r l mo mo mo mo mo mo mo d C C C C C C C C C S S C C C C C C C C C o S C C C C C C C eu n it t d e d e d e d d d d d d d d n o n t c a l a t a t a e t a e t a e t a e t a e t a e t a e t a e t a s s s s s s s s s s 4 4 4 4 4 4 4 2 . 3 u l u l u l u l u l u l u l u l u l u l u l u d a d a d a d a d a d d d d d a K KK KK KK 3 0 1 m e i l t mit m s it m s it m s it m s it m s it mit mit mit mit mit e b e e e e a e a e a e a e e S a b a b a b a b a b a b a b a b a b a C S 3 C S 3 C S 3 C S 3 C S 3 C S 3 C 9 1 3 0 9 b S - a n -n -n -n - s n - s n - s n - s n - s n - s n -n n n n n n n n n n n mmmmmmm 7 4 1 T U U U U U U U U U U U y Dy Dy Dy Dy Dy Dy Dy Dy D y D a P a P a P a P a P a P a P / 1 B D 0 5 O W-2 1 2 . 6 0 0 . 0 5 - ± 2 1 . ± 4 2 6 . 0 6 . 3 1 0 0 3 1 ) e n o l a n o 0 1 < i . R < R t a l ) u s n 0 O O o O Om it i t s i t d s n ni o a c g d a e t n a l o i t u m ) ) 0 i n n 0 a l ts o i o i ± ± 0 0 0 1 . . u - s m n 0 0 i t s u s s t e s r s e g r g h n e R e ti i a c R c R wt g n a i t s i t O e n mo i s O t i g i o g o s it 7 a t a l L u ( L n 7 e ( R i o 2 3 6 . 1 . e rt mi v e r v r O p d ± 1 1 9 . 4 ± ± g n t i s u C u C O e ri h 1 9 . 1 . r a g ni d r d r r a t 7 2 p e 1 m r o a a d a d s t h t c p n ( m a t n a n t i o s p a 1 o c S S r s t 0 ( e 0 h e 0 1 h e n i 0 0 t t h t o p . 0 e v w o a M µ O S 0 0 0 . o b o l s e at t a d 3 < 0 M M $ p 0 < A e B e n i o o 0 . 0 µ D_ ; 1 p g n g n p w a tf _ 0 1 l o r 0 0 ; 1 a R a R t a o 8 _ t 0 . 0 f d e d e l n 0 0 f e g n u o o r o c < 0 . o o 0 t t l g a r e p o b t n p * < u Ou Oni s v a ma o s e i C r v l * * C o S ; † 1 †p † 0 ; 0. 1 0 0 < 0 . a 0 t a 4 K 4 4 p * < D S K * † p d e a 2 . 3 C S K S ; † 3 C m 3 C 3 1 ; 0 . 1 n i t 0. > < l r a 0 9 1 e D 0 9 7 a ma m0 0 R OR Od n d l o 4 1 P P a P < p < * † p O O U B / 1 B D Table 13 continued. Cytokine Results in PBMCs (Donor 1) Stimulant Sample ID IL-23 TNFα Un-stimulated Compound 8_10 µM OOR< 2.8 ± 3.7 Un-stimulated Compound 8_3 µM OOR< 0.4 ± 0.1 Un-stimulated Compound 8_1 µM 5.11 0.5 ± 0 Un-stimulated Compound 8_0.3 µM OOR< 1 ± 0.2 Un-stimulated Compound 8_0.1 µM 14.50 31.5 ± 40.1 Un-stimulated Compound 8_0.03 µM OOR< 2.3 ± 0.8 Un-stimulated Compound 8_0.01 µM OOR< 7 ± 3.8 Un-stimulated Compound 8_0.003 µM OOR< 14.3 ± 16 Un-stimulated Crisaborole_10 µM OOR< 0.6 ± 0 Un-stimulated Solvent control_DMSO OOR< 9.9 ± 4.2 Un-stimulated Standard OOR< 11.2 ± 10.9 Dynabeads Compound 8_10 µM OOR<* 22.8 ± 26.9*** Dynabeads Compound 8_3 µM 296.2 ± 40 2051.8 ± 293.7 Dynabeads Compound 8_1 µM 343.9 ± 30.3 4228 ± 894.3 Dynabeads Compound 8_0.3 µM 289 ± 107 3699.5 ± 979.3 Dynabeads Compound 8_0.1 µM 341.1 ± 70.8 2358.6 ± 233.2 Dynabeads Compound 8_0.03 µM 438 ± 32.1 3124.6 ± 991 Dynabeads Compound 8_0.01 µM 335.3 ± 49.5 2595.7 ± 553.2 Dynabeads Compound 8_0.003 µM 369.6 ± 100.5 3275 ± 1150.4 Dynabeads Crisaborole_10 µM 438.2 ± 142.2 272.4 ± 97.1*** Dynabeads Solvent control_DMSO 374.6 ± 140† 2213.3 ± 139.9††† Pam3CSK4 Compound 8_10 µM OOR< 0.5 ± 0.4* Pam3CSK4 Compound 8_3 µM OOR< 0.2 ± 0* Pam3CSK4 Compound 8_1 µM OOR< 1.5 ± 0.7* Pam3CSK4 Compound 8_0.3 µM OOR< 5.7 ± 4.1 Pam3CSK4 Compound 8_0.1 µM OOR< 5.9 ± 4.1 Pam3CSK4 Compound 8_0.03 µM OOR< 8.5 ± 2.9 Pam3CSK4 Compound 8_0.01 µM OOR< 19.3 ± 7.3 Pam3CSK4 Compound 8_0.003 µM OOR< 26.9 ± 9.7 Pam3CSK4 Crisaborole_10 µM OOR< 0.8 ± 0.1* Pam3CSK4 Solvent control_DMSO OOR< 14.9 ± 3.2 *p< 0.01; **p<0.001; ***p< 0.0001; $p< 0.00001 (comparing treatment with stimulation against stimulation alone) †p< 0.01; ††p<0.001; †††p< 0.0001; p< 0.00001 (comparing stimulation against un-stimulated conditions) OOR > Out of Range Above the Standard Curve (Logistic Regression) OOR < Out of Range Below the Standard Curve (Logistic Regression) Underlined Data single data point as other points are OOR Bold Data average of two data points as the third point is OOR DB1/ 147901903.2 278 0 5 O W- * 2 1 0 5- 2 7 6 8 9 5 6 8 6 $ * 1 * 8 . . 9 . 4 3 4 . 3 9 . 4 . 7 . 6 1 7 2 2 3 5 6 . $ 3 8 . 2 . 7 5 0 . 0 . 3 . 1 1 . 0 . 4 . 2 . 1 1 . . 0 6 6 7 0 1 1 3 2 5 7 0 2 5 1 < 0 . 2 2 . 1 9 . 1 9 . 3 5 . 3 4 - 0 6 L I . 0 ± ± ± ± ± ± ± ± 4 ± 1 2 ± ± ± ± ± ± 8 5 . ± ± ± ± 8 2 9 5 9 . 5 ± R 2 O3 . 0 ± ± ± ± ± 3 0 . 3 0 8 . 3 8 . 3 1 8 . 2 5 . 6 6 . 4 6 . 2 5 2 . 4 2 . 9 1 2 . 8 . . 5 8 7 9 . 2 3 . 4 . 5 0 . 6 4 6 7 6 9 5 3 9 9 . 0 8 O 7 4 . 3 1 . 2 1 . 4 6 . 7 8 . 9 1 8 9 5 1 4 5 5 5 5 5 1 1 5 6 . $ * * 3 . 2 . 3 . 1 2 β 1 0 1 . 1 1 3 - ± 0 . 0 . 0 0 ± . 0 6 3 1 . 3 2 . 4 0 . 3 0 . 0 4. 9 0 1 8 . * 3 8 2 6 6 9 1 . 6 3 . 2 0 0 0 2 . 4 . 1 . 0 6 . 4 1 ± ± ± 1 ± ± ± ± ± ± ± ± 3 1 ± 2 2 4 ± ± ± 6 ± ± ± ± ± ± ± 0 1 1 1 ± 1 7 ± ± ± L I . 0 4 . 2 . 1 . . 0 3 . 6 . 5 . 3 . 6 . 3 . 5 . 8 3 . 5 . 7 . . 5 . 6 . 4 . 4 . . 0 . 0 . 0 6 . 3 . 1 . 0 0 0 0 2 2 1 0 0 0 . 0 4 2 3 1 2 0 5 7 6 1 5 4 4 1 6 6 0 0 1 2 6 2 4 7 2 9 . 5 . 2 . 9 . 6 . 2 . 5 . † 3 γ 0 1 . 0 0 0 0 1 . 3 . 0 8 . 1 . * 9 2 6 6 5 5 9 3 2 1 7 5 0 7 4 0 4 3 7 * 5 4 . . 6 0 1 . 1 . 1 . 1 . 3 . NF ± 0 0 0 0 0 . ± ± ± ± ± ± ± ± ± ± 0 9 I 1 . 0 1 . 1 0 . 0 1 . 0 1 . 0 3 . 0 3 . 3 0 . 1 0 . 0 7 . 2 0 . ± 1 2 ± 1 2 3 1 2 3 ± ± ± ± ± 2 9 0 ± ± 0 0 0 0 4 0 ± ± ± ± ± ± 0 7 ± . 8 . 9 0 6 8 8 . 4 . 7 . 7 . 6 . ± 2 1 . 1 . 1 . 2 . 3 . 3 . 8 5 8 6 5 . 3 0 0 0 0 0 . 2 . 0 6 5 4 5 1 0 7 4 6 6 0 2 6 9 6 8 4 8 4 2 9 6 5 8 3 1 4 9 7 F S 3 3 6 1 5 1 1 1 6 * * * 8 3 . 9 2 . 4 . 7 7 . 8 7 . 4 9 . * 0 * † 2 4 † 4 5 . 1 1 4 2 2 4 . 8 C < - R . 0 . 0 . 0 . 0 . 0 7 . 3 . 2 . 0 . 1 . 0 6 . 5 2 3 0 1 1 0 1 4 . 0 0 8 . 0 . 0 . 0 . 0 . 1 3 1 . 1 MO± 6 ± 5 ± 8 ± 6 ± 9 ± ± 6 ± 4 ± 8 ± 3 ± ± ± 1 ± 7 . 1 7 ± ± ± 1 2 7 ± 2 ± ± ± 3 ± 3 ± 9 ± 5 ± 7 ± ± 4 G O. 0 . 0 . 0 . 0 . 0 3 . 2 . 0 . 1 . 1 6 . . . 2 2 6 . 4 3 2 4 5 5 6 5 . 9 2 5 . 4 6 . 2 . . 0 . 0 . 0 . 0 . 2 3 . . 5 6 1 7 6 6 2 8 9 0 3 2 0 1 ) 7 2r o n o D ( MMM µ MM O µ µ S MMMMM µ O S MMMM s M M I MM µ µ 3 MM MMM µ µ µ µ 3 MMMMM µ µ µ µ C D µ el 0 µ µ 3 1 3 0 1 0 0 0 D µ µ µ 3 1 3 0 1 0 D µ 3 1 1_ 3 _ 1 . _ 0 . _ 0 . _ 0 . _ 0 . _ 0 µ _ _ 0 l 0 o 1 _ 3 _ 1 . _ 0 . _ 0 . 0 _ 0 . 0 _ 0 . _ 0 µ _ _ 0 l 0 µ µ 3 o 1 _ 3 _ 1 . 1 0 . 0 0 . 0 0 . 0 B p 8 8 8 8 8 8 8 8 1 rt 8 8 8 8 8 8 1 rt _ _ _ _ _ P m i d d d d d d d d _ e l n 8 8 _ e n 8 8 8 8 8 8 8 n a s S n n n n n n n o d d d d d d d d l o d d d d d d d t l u u o u u u u u u n u o r s p o p o p o p o p o p o p o p o c b t d n r n a u n o u n u n u n u n u n u n u o r c t n u n u n u n u n u n u n u p o p o p o p o p o p o p o p o b n o p o p o p o p o p o p o p e mo mo mo mo mo mo mo ma o s e i r v l d n a mo mo mo mmmmma s e i v l mmmmmmm R C C C C C C C C o t o o o o o r o S o o o o o o o e C S S C C C C C C C C C C C C C C C C n i k o t d d d d y t n e t a e t a e t a e t d a e t d a e t d a e t d a e t d a e t d a e t d a e t a s 4 4 4 4 4 4 4 C a . l u l u l u l u l u l u l u l u l u l u l u l u s d s a d s d s d s d s d s d s d s d d K KK KK KK 2 . 3 4 1 m i e t mit m l S s i - t mmmmmmmmme a e a e a e a e a e a e a e a e a e S s it it it it it it it it it b a b a b a b a b a b a b a b a b a b a C S 3 C S 3 C S 3 C S 3 C S 3 C S 3 C 0 3 9 1 0 b n - s n - s n - s n - s n - s n - s n - s n - s n - s n -n n n n n n n n n n n mmmmmmm 9 7 4 a U U U U U U U U U U U y Dy Dy Dy Dy Dy Dy Dy Dy D y D a P a P a P a P a P a P a P 1 T / 1 B D 0 5 O W-2 1 0 5 2 - . 6 7 . 9 7 . 4 4 6 ± ± ± 8 8 4 . 2 . 4 . 3 . 8 $ 5 4 8 3 8 3 0 . 1 4 4 . 7 . 8 6 . 8 . 9 . 7 . 0 . 8 4 . 5 8 . 0 1 8 5 . 9 - 0 . 8 . . 0 1 1 . ± ± ± 8 9 4 3 6 1 7 9 1 5 1 7 8 2 1 1 1 2 . 0 1 7 9 7 3 3 0 1 7 2 1 ± ± ± ± ± ± 2 ± ± ± ± ± ± ± ± ± 3 ) e L I n 1 . 8 7 . 5 7 8 9 2 . 8 1 5 2 8 . 3 . 9 . 1 8 . o 6 . 5 0 l 1 . 0 . . 9 9 7 2 . . 9 a 6 3 3 6 8 6 6 9 . 6 1 9 . 3 4 . 5 5 0 2 6 1 7 1 3 4 1 3 4 7 9 3 6 8 3 6 6 3 6 5 3 7 6 3 n 1 1 1 oi t a ) 2 . 2 . l s ± 4 5 1 m i o t i t i * 7 * * * * 9 . 9 . 2 . 6 . 6 . ± 6 9 ± 4 s t d 2 . 8 . 3 s n o 0 1 . 2 3 1 . 0 . 0 . 0 . 6 1 . 5 . $ 0 6 . 6 . 6. 3 . 1 . 8 0 1 5 0 8 0 1 4 7 1 3 n i a c 6 g d - 0 1 ± 0 a e t L I . 0 1 . ± ± ± ± 4 6 3 0 0 4 2 1 ± ± 0 2 . 4 ± ± ± . 7 . 1 . 8 . 3 . 1 . ± ± ± 4 2 9 ± ± 2 7 ± ± n a l ) ) 0 0 0 2 0 o 3 5 1 . 0 2 . 2 . . 6 . 9 . 8 . 3 6 0 5 8 1 i 6 3 5 t u n a m o n o 0 8 2 4 4 6 5 l it i s s i s 1 1 5 ± . 1 1 . u s- 0 m i n e u r s e g r e g e * 8 . 1 1. ± ± t s t 1 1 . 3 . h s ti n R i c R c R 0 1 . 0 3 . 0 4 . 0 < 1 . 4 0 . 0 * 2 6 . 3 4 . 3 . 1 2 4 . 3 8 . 9 . 8 6 w a i i O 5- 2 4 0 ± 0 R 3 ± ± ± 2 2 1 0 t g t s ts O L 0 . 0 . 0 . 0 . ± ± ± O± ± 2 ± ± ± n a i i e n g o o g L o s i I 0 0 0 1 . 0 0 1 . L t 0 2 . 0 3 . 0 O1 . 3 ± 3 0 . 0 4 . 7 . . . 6 3 9 8 3 4 4 4 1 4 9 1 7 1 3 3 1 mt i a t a ( ( n i o 1 1 0 8 e l u e v e v R O p 2 r 6 t m r . 5 it u r 4 . 4 2 . 6 g n s C u O d ri ± ± ir g d C e r r h t a d r a a ) 7 s e 2 2 * . 8 5 . 5 2 . 3 6 . 3 3 . 6 9 . 0 5 ± a . 4 . 5 . p nir d n d t h n n i t s r o 4 < R 0 < 0 R 9 9 0 0 ± < 1 . 0 * 6 0 . 1 5 9 8 1 9 4 ± 1 7 2 9 m o a p a t a t o p a s n o - L 3 I O. 0 0 O. 0 1 0 R 5 0 . 0 . 0 . 1 1 O. 1 ± 2 ± ± ± 4 4 ± 9 . ± c( m S S r t D O O . 0 O 3 . ± 3 . . 7 . 2 . 4 6 . 1 o 0 c ( e h e h e 0 t t h n t i ( o p s 0 8 4 4 2 9 8 7 7 8 0 1 2 0 1 0 e C 5 8 9 9 1 9 v w o o s a t M M µ O 0 S . 0 0 0 o b l e at a B < 0 . A B n i d o P 30 MM . $ p 0 e g e g o p w n t i s MMM µ O S MM 0 0 µ D _ 0 _ l ; < p n n a f tl M M 8 1 _ o 1 0 ; a R a R t a o µ M µ µ µ 3 M M M µ M µ µ e u s D µ MM 0 µ µ 3 . 1 . 3 0 . 1 0 . 0 0 M . µ D µ M µ M µ µ 3 1 3 0 1 0 e rt n 0 0 . 1 0 f o f o d e g a e R I e 1 _ 3 _ 1 _ 0 _ 0 0 0 0 0 _ l 0 . . . . o 1 3 1 0 0 0 0 d l o 0 t t l r l 8 8 8 _ _ _ _ 1 rt _ _ _ _ _ _ _ n o c 0 0 . u u g e e p 8 8 8 8 8 _ e n 8 8 8 8 8 8 8 u o r p o b t n < e p 0 * < O Oni s v a n i k md o a n d u n d u n d u n d u n d u n d u n d u n l u o r o c d t d r n d u n d u n d u n d u n d u n d u n u ma s v * p t S o o o o o o o o o b n a o o o o o o o o i r l *† 1 † y p p p p p p p p a e d p p p p p p p C C o S ; † C mmmmmmmms 0 ; 1 . i v l n mmmmmmm d o C o o o o o o o r o a t o o o o o o o 0 . C C C C C C C C S S C C C 0 0 0 . a t e C C C C u 4 K 4 4 < p 0 a n i * < p D t d n t e t d S K C S K S * † † d e a t o c n a l a e l t d a e l t d a e l t d a e l t d a e l t d a e l t d a e l t d a e l t d a e l t d a e l t a l s d s d s d s d s d s d s d 2 . 3 0 3 C 3 C ; 3 1 ; m 0 . 1 0 . > < n il r a a m e D 4 1 u u u u u u u u u u u u mi mit mmmmmmmmmma e a e a e a e a e a e a e 9 1 s it s it s it it it it it it it it b a b a b a b a b a b a b a 0 9 P a m P a 0 0 R P < p < OR Od n d l e l t S -n -n - s n - s n - s- s- s- s- s- s - n n n n n n n 7 4 1 * † p O O Uo B b a n n n n n n n y y y y y y y T U U U U U U U U U U U D D D D D D D / 1 B D 5 0 5 O W-2 1 0 5 - 3 4 . 6 . 3 . $ $ $ 5 6 1 . 2 . 8 7 . 7 . 1 . 5 . 7 . 1 . 3 3 4 3 8 5 5 . 9 . 1 5 8 5 0 1 0 6 ± ± ± 0 7 5 4 2 5 2 1 ± ± 2 6 0 ± ± ± ± ± ± ± ± 3 1 2 . 1 0 . 5 . 3 2 1 . 9 . 8 4 . 6 . 7 . 8 . 3 . 7 4 . ) 7 8 8 3 6 9 3 6 0 3 2 0 . 3 1 7 5 1 2 9 5 1 4 4 6 2 6 8 3 6 4 3 6 9 3 6 4 3 6 5 3 4 6 e 3 n o l a n o i t a l ) u s n 7 . 1 6 2 6 3 2 † moi t 5 9 5 1 8 1 . 1 * 1 * * 1 * * * . . . . 3 * * . † 5 8 0 . 1 0 3 7 7 8 . it s i d 1 9 4 2 1 3 9 9 t s n o ± ± ± . 0 . 0 . 0 7 1 ± ± ± 7 n i c 1. 1 3 . 2 7 9 . ± ± ± ± ± ± 6 9 . 8 . 1 . 8 . 3 . ± 4 5 . a g d e ) t n ) n 8 9 4 7 3 5 4 . 7 0 . 6 . 0 . 3 9 3 8 6 8 2 7 4 9 2 7 6 1 1 6 1 9 a a 1 0 6 n l o i o s o i i s t u s a m e s e l it r u s - g r e g R e R 9 * † † 3 . m i n t u t c i ± * 3 5 0 2 . s t c R i O h s n si tsi O 4 . . 0 2 1 ± 4 0 . 0 0 0 . 1 . 4 0 0 1 4 0 ± 0 1 0 0 ± ± ti i a g o g o s i 3 ± 1 2 . 9 3 . 0 0 0 . 0 . 0 . 0 1 . . 5 0 0 0 2 . w t g a L ( L ( t n i 6 0 n o 1 e n mo t i e v e v R p 1 a t a r e l u r Od 8 r C u O ri 2 6 t u m . it d C e r d r r a h t e 1 5 * † † g ni s a d a d s t n h t 1 * 8 9 ± . . 6 6 2 r 1 9 8 < 0 . 0 a g p n n i a n r t a i S t o s S p a s 8 1 0 . ± . 5 . R 9 0 . ± 0 6 9 . 0 4 0 . 3 . 3 . ± ma p e e r e t n i 7 7 3 . ± 0 0 O 0 1 0 5 4 O . 0 0 0 0 0 8 . o c ( m h o t h t h t o o p 1 2 5 0 9 1 0 c ( e v 0 1 o w b o l s a t e a a 0 0 0 . A B t n i d o M 0 0 0 0 e e o µ O S . g w MMM µ O S < p 0 n g a n p a a t ta f o 3 0 0 MMM MM µ µ . µ MM µ µ 3 1 3 0 MM $ ; < 1 p R f R o f o d e e g a 0 µ D_ _ 0 l 0 1 µ µ 3 . 1 . 0 . 0 . 0 . µ D_ l 0 0 ; 1 t u t l u g r e 8 1 ort _ 3 _ 1 _ 0 _ 0 _ 0 _ 0 _ 0 _ 0 1 or 0 . 0 0 O Oni s v a d _ e n 8 8 8 8 8 8 8 8 _ e t n 0 0 n l u o r o c d n d d d d d d d l u n u n u n u n n n n o r o c < . p 0 o p o b t n e o p o p o p o u p o u p o u p o u p o p o b t n * * < † p ma o si v mmmmmm as e v * ; † † C r l C o S o C o C o C o C o C o m C o m C o i C r l C o S 1 0 ; 0. 1 0 0 < 0 . a 0 t a sd s s 4 4 4 4 4 4 4 4 4 4 p * < D a d d * † p d e a 2 . 3 e a a K S K S K S K S K S K S K S K S K S K S ; † ; n i t a 0 9 b e a b e b C n a 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 1 0 . 1 0 > < l r D 1 0 9 y n a y n 3 y mmmmmmmmmm0 . 0 R OR e Od n d l 7 o 4 1 D D D a P a P a P a P a P a P a P a P a P a P < p < * † p O O U B / 1 B D 0 5 O W
Figure imgf000283_0001
-2 1 0 5-4 6 3 A 0 7 < 1 8 . 2 . 4 . 2 . 3 . $ 6 . 1. 4 9 . 1 1 3 5 . 0 1 . 3 1 - R 2 O1 7 . 3 5 8 0 1 ± 0 2 0 0 0 0 . 0 . 1 . 1 ± ± ± ± ± 3 1 4 < ± ± ± 3 . ± R 0 7 O1 . 0 0 1 0 . ± I O 0 . 1 9 8 . 1 4 . 0 2 . . 0 2 9 . 3 1 O 0
Figure imgf000283_0002
1 0 7 9 0 1 2 1 . 4 . 8 3 2 0 3 R < R 1 0 0 . 2 < R 0 . 0 3 2 < R < R 9 0 1 1 . 0 . ± ± O3 . ± ± 7 ± OO0 . ± I O O 0 1 3 . 1 2 O 7 . 0 . 1 . 1 0 O 0 1 . 3 3 1 2 1 1 1 . 1 . 1 . 1 . 5 . 5 . 0 0 0 0 1 ± ± ± 1 0 0 ± 0 0 . 0 9 4 0 ± 0 . ± ± ± ± ± ± ± ± ± 2 1 0 1 . 1 . 8 . 2 . 1 . 1 . 1 . 1 . 2 . 1 . 5 . 0 1 . ± I 0 0 0 0 0 0 0 0
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* ) 5 6 . . 6 1 5 . 5 . 4 . 7 † . * † 7 2 0 * 1 9 . 4 . 7 . 8 . 6 . * 2 9 7 9 no 1 4 4 4 2 1 2 2 9 1 0 3 * 8 4 2 * 1 * * * * - < * 0 ± 1 3 4 3 0 1 1 ± ± ± ± ± . 2 1 ± ± 5 ± ± ± 5 3 ± ± ± * * * * 7 . 0 D ( I O O 0 . 1 3 . ± ± 2 3 5 2 . 6 3 . 6 7 . 2 9 . 5 1 . ± ± 8 . 6 6 . 6 . 2 . 9 3 5 5 5 . 8 0 0 . 3 . 7 . 2 . ± 5 7 8 1 4 8 7 0 3 6 4 4 . 4 6 9 0 0 2 . 9 s C 9 7 9 0 1 0 M 4 1 1 2 2 1 2 1 2 1 9 0 2 1 B P
Figure imgf000283_0006
Figure imgf000283_0007
n i MMM O s S MMM O S MM tl M MM µ µ µ µ MM µ µ 3 MM MMMM µ M µ µ µ µ 3 MMMMMM µ M µ µ µ u s e D I 0 e 1 µ _ 3 µ _ 1 3 . _ 0 1 . 3 _ 0 0 . 1 _ 0 0 . 0 _ 0 0 . _ 0 µ D µ _ _ 0 l 0 o 1 µ _ 3 µ _ 1 3 . _ 0 1 . 3 _ 0 0 . 1 0 0 . 0 0 0 . 0 µ D µ 0 _ l 0 o 1 µ 3 µ 1 3 . 0 1 . 3 0 0 . 1 0 0 . 0 R l 8 1 rt _ _ _ _ 1 rt _ _ _ _ _ _ _ en p 8 8 8 8 8 8 8 _ i m e n 8 8 8 8 8 8 8 8 _ e n 8 8 8 8 8 8 8 d n d n d n d n d n d n d n d n l o o d n d n d n d n d n d n d n d n l o o d n d n d d d d d ko a t S u u u u u u u u r y o p o p o p o p o p o p o p o p o c b t d r u u u u u u u u r c t u u n u n u n u n u n u C a n e a d o p o p o p o p o p o p o p o p o b a n e o p o p o p o p o p o p o p mmmmmmmms v n mmmmmmm s v . d o o o o o o o o i r l o a o o o o o o o mo i r l mo mo mo mo mo mo mo e C C C C C C C C C S t S C C C C C C C C C o S C C C C C C C u n it d d d d d d n t o n e c a t l a e l t a e l t a e l t a e l t a e l t d a e l t d a e l t d a e l t d a e l t d a e l t a l s 4 u u u u u u u u u u u u d s d s d s d s s s s s s d 4 4 4 4 4 4 4 2 . m a a a a d a d a d a d a d a a K 1 m i mi mi mi mmmmmmme e e e e e e e e e S K C S K C S K C S K KK 3 C S C S C S C 0 9 1 e i l t t s - t s - t s - t s i - t s i - t s i - t s i - t s i - t s i - t s i - t s b - a b b b b b b b b b n a n a n a n a n a n a a a a 3 3 3 3 3 3 3 0 9 b S n n n n n n n n n n n y y y y y y n y n y n y n y ma ma ma mmmm 7 4 a U U U U U U U U U U U D D D D D D D D D D P P P a P a P a P a P 1 T / 1 B D 0 5 O W-2 1 0 5-4 6 4 . 3 1 0 5 . 0 3 ± ± 7 1 8 . 6 2 . ± 1 9 ) e n o l a n o i t a l ) u s n mi oi t 7 . t 0 8 s i t d n ± ± ± s o 5 n i c 6. 4 3 . 1 . 6 a g d a e t n a l ) ) o i t u n o i n o i a m l it s s s s u s - e r e m r i n g g t u e e 2 . 1 s t s R R R 0 0 . h n c i c i O ± ± 0 t 1 ± i i w a t g si t si O 3. 0 . 0 2 . 0 t n a e n g o g o s i t mo t i L a t ( L a e ( n e R i o 3 8 e l v v O p 2 rt u r mi u r u O dr * g n ts C d C d e i r a h t 9. 5 * 3 † † † ir g r a r a s t e h t ± . 4 5 . a p nir d n d n n i s 2 6 . ± 9 ± m o a p a t a S t o S p a s 4 1 . 8 2 9 6 c ( m 1 o e r t h e e n i 0 c ( t h t h t o 0 1 e w o p 0 0 0 v . 0 o b o l s e a a t t a d Mµ O 0 0 S < 0 . 0 A e B n e i o o 3 w 0 $ p g n g n p t 0 MM; < .0 µ D_ a a a t f _ 0 l 1 p 0 ; R f R f a d o e 8 1 o r 0 0 . 1 0 o o e l g a r d _ e t n l n 0 0 0 t u t u g ni e v u o o r o < . O O p o c b t p 0 s a * < a n e * † p mo si v l * ; † † C r C o S 1 0 ; 0. 1 0 0 0 . a t 4 4 4 < p 0 a < D K S K K *† p d a 2 . C S 3 C S * † e t 3 3 C ; ; 3 1 n m 0 i a 0 9 . 1 0 . > < l r a m e D 1 0 9 7 P a m P a 0 0 R P < p < OR Od n d l 4 1 * † p O O Uo B / 1 B D 5 Table 14 continued. Cytokine Results in PBMCs (Donor 2) Stimulant Sample ID IL-23 TNFα Un-stimulated Compound 8_10 µM OOR< 0.2 ± 0.1 Un-stimulated Compound 8_3 µM OOR< 0.3 ± 0 Un-stimulated Compound 8_1 µM OOR< 0.8 ± 0.2 Un-stimulated Compound 8_0.3 µM 2.43 4.5 ± 2.5 Un-stimulated Compound 8_0.1 µM 5.11 3.9 ± 2 Un-stimulated Compound 8_0.03 µM OOR< 18.2 ± 11 Un-stimulated Compound 8_0.01 µM 325.36 35.9 ± 35.8 Un-stimulated Compound 8_0.003 µM 21.25 57.1 ± 53.7 Un-stimulated Crisaborole_10 µM OOR< 0.5 ± 0.1 Un-stimulated Solvent control_DMSO 10.49 46.6 ± 41.7 Un-stimulated Standard OOR< 17.5 ± 0.8 Dynabeads Compound 8_10 µM OOR< 6.1 ± 4.5* Dynabeads Compound 8_3 µM 370.6 ± 238.4 2056.7 ± 340.4 Dynabeads Compound 8_1 µM 176.4 ± 47.9 2818.1 ± 297.8 Dynabeads Compound 8_0.3 µM 267.9 ± 158.5 2541.7 ± 382.7 Dynabeads Compound 8_0.1 µM 341.9 ± 116 2678 ± 326.3 Dynabeads Compound 8_0.03 µM 173 ± 34 2200 ± 382.1 Dynabeads Compound 8_0.01 µM 233.5 ± 133.3 2286 ± 150.2 Dynabeads Compound 8_0.003 µM 222.7 ± 49.7 2924.1 ± 635.6 Dynabeads Crisaborole_10 µM 264.1 ± 58.3 38.4 ± 6.2* Dynabeads Solvent control_DMSO 184.7 ± 98.9 2855.2 ± 604.1† Pam3CSK4 Compound 8_10 µM OOR< 0.3 ± 0.1$ Pam3CSK4 Compound 8_3 µM OOR< 0.5 ± 0.2$ Pam3CSK4 Compound 8_1 µM OOR< 3 ± 1.4$ Pam3CSK4 Compound 8_0.3 µM OOR< 15.3 ± 3.1$ Pam3CSK4 Compound 8_0.1 µM 18.60 59.8 ± 13 Pam3CSK4 Compound 8_0.03 µM 248 ± 150.5 150.3 ± 59.5 Pam3CSK4 Compound 8_0.01 µM 23.7 ± 32.2 118.4 ± 4.5 Pam3CSK4 Compound 8_0.003 µM 40.3 ± 36.8 120.1 ± 14.3 Pam3CSK4 Crisaborole_10 µM 3.80 7.5 ± 2.2$ Pam3CSK4 Solvent control_DMSO 5.11 134.7 ± 4.8 *p< 0.01; **p<0.001; ***p< 0.0001; $p< 0.00001 (comparing treatment with stimulation against stimulation alone) †p< 0.01; ††p<0.001; †††p< 0.0001; p< 0.00001 (comparing stimulation against un-stimulated conditions) OOR > Out of Range Above the Standard Curve (Logistic Regression) OOR < Out of Range Below the Standard Curve (Logistic Regression) Underlined Data single data point as other points are OOR Bold Data average of two data points as the third point is OOR DB1/ 147901903.2 284 0 5 O W-2 $2 1 0 5 . 1 . 4 . 1 . 3 . 1 . 8 8 . 8 . 5 . 9 . 5 . 8 1 5 3 6 9 6 1 2 4 . 6 3 . 2 3 . $ 5 9. 8 1 . 1 5 7 5- 2 0 1 2 1 1 2 5 . 0 . 3 2 7 . 0 7 1 4 3 3 1 7 5 1 ± ± ± 1 1 9 ± . 0 0 . 2 1 . 1 . 0 1 3 . 1 4 - L 1 I . 0 ± 3 ± 9 ± ± ± ± 8 ± ± ± 7 . ± ± ± ± ± ± 8 5 4 7 4 . 1 . 1 . ± 1 . ± 2 . 0 ± ± 1 ± ± 5 . ± 6 3 0 . 3 2 . 5 2 . 1 1 . 2 3 . . 1 4 1 1 . 4 6 . 8 6 0 1 6 . . 6 1 . 8 . 7 . 3 2 5 5 8 8 9 2 0 0 1 8 3 6 2 . 9 2 6 2 2 2 0 7 3 2 . 9 . 4 . 0 3 0 3 4 1 9 8 . 8 1 1 5 5 6 6 6 6 6 5 6 8. * 4 . 9 . 2 . 6 . 3 2 † † 6 β1 0 0 1 ± ± . 0 0 2 ± . 0 0 7 ± 1 1 1 . 3 0 . 3 0 . 0 3 . * 3 5 5 . 2 8 2 3 1 5 . 2 6 . 1 9 1 6 1 * 1 . 4 . 0 ± 8 9 1 1 . 0 0 8 ± . 8 6 . 8 0 . . 0 5 0 8 . 1 1 - 1 1 ± 1 ± 2 ± ± ± ± ± ± ± ± ± ± ± 2 ± ± ± ± ± ± ± ± L I . 0 . 0 3 . . 0 2 . . 0 2 3 . 3 . 4 . 5 ± 7 . 1 . 1 . 5 . 2 . 2 . . 7 7 . 2 . 2 . 2 . 8 . 1 . 2 . 3 9 . 0 0 . 1 7 0 0 0 6 . 2 7 5 8 7 1 0 1 1 6 1 3 1 1 1 1 1 3 1 2 1 4 9 3 5 0 0 4 1 3 . 7 2 1 3 8 4 . 2 4 6 6 8 . 2 8 . . 3 5 . . 7 . †7 γ 0 1 . 1 . 2 . * 7 5 3 7 1 6 1 9 6 9 3 8 2 1 3 * 0 6 . 4 1 1 . 1 . 2 . 1 . 2 . 1 . 2 NF ± 0 0 0 0 0 1 I 1 . ± ± 0 1 . 1 0 . ± ± ± . 1 0 0 0 0 . 0 1 . 1 0 . 1 0 . ± ± ± ± ± 4 1 2 7 3 ± 1 ± 1 1 9 1 ± 0 0 0 0 0 0 . 0 0 1 3 . 1 0 . 2 0 . 1 0 . ± ± ± ± ± ± ± ± ± 0 2 . 3 3 . 9 5 . 5 . ± 2 . 9 . ± 4 ± ± . 7 . 9 . 7 ± . 2 1 2 2 3 5 4 3 8 1 4 9 8 5 7 2 . 0 . 0 . 0 . 0 . 0 . 0 . 0 0 0 4 1 8 3 4 2 4 3 0 2 9 1 2 4 5 2 6 6 0 3 9 3 5 8 2 $ * * * * 4 2 7 7 . 7 * * F S 2 . 2 3 3 6 4 3 1 1 5 7. 8 . 7 . . . . 6 . * 1 . 1 7 C 0 . 0 . 0 - ± ± ± 0 . 5 0 . 0 . 4 . 0 . 0 . 0 . 0 2 6 2 7 ± ± ± ± ± ± ± 1 4 7 0 2 7 2 9 4 ± ± ± 1 4 4 2 . ± ± 3 3 4 2 . ± 0 0 . 3 0 ± ± ± 0 . 7 7 0 . 4 1 ± M3 3 8 . 0 5 7 8 8 8 ± ± ± 3 8 9 8 ± 8 3 . . 0 ± ± 4 . G . . . . . . . . 7 . 3 . 3 5 1 1 . . . 1 . . 4 9 8 6 0 0 0 0 0 3 0 0 0 1 . 1 . 2 . 5 3 2 . 7 5 9 9 . 0 . . . 2 ) 2 7 9 6 9 4 . 0 0 0 4 3 2 0 5 5 6 6 0 8 6 6 0 2 1 7 ro n o D ( M O M O MMMMµ S M MMµ S MM s C M D µ M µ M µ µ 3 µ µ µ 3 M M 1 3 0 1 0 0 0 M D µ MM µ M µ µ 3 µ 1 3 0 MMM M D µ MM µ M µ µ 3 µ 1 M I B e l 0 1 _ 3 _ 1 . _ 0 . _ 0 . _ 0 . _ 0 . _ 0 µ _ _ 0 l 0 µ µ 3 o 1 _ 3 _ 1 . 1 _ 0 . 0 _ 0 . 0 0 . 0 0 . 0 µ 0 _ l 0 µ µ 3 . 1 . 0 . 0 . o 1 3 1 0 0 0 0 P p 1 rt 8 8 8 8 _ 8 _ 8 _ 8 _ 8 1 rt _ _ _ _ _ _ _ n m8 d 8 d 8 d 8 d 8 8 8 8 _ e n _ e n 8 8 8 8 8 8 8 i a n n d d d d l o d d d d d d d d l o d d d d d d d st l S u u n u n u n u n u n u n u o r c d n u n u n u n u n u n u n u n u o r c n u n u n u n u n u n u n u u o p o p o p o p o p o p o p o p o b t n r a o p o p o p o p o p o p o p o p o b t n o p o p o p o o o o s a R o C o C o C o C o C o C o C o s e i r v l d o a t o o mo mo mo mo mo ma e o i r v p p p p e mmmmmmmm n mm s l o mo mo mo mo mo mo mo e n C C S S C C C C C C C C C S C C C C C C C ik o t y t d C n e a t d . l a e l t d a e t d a e t d a e t d a e t d a e t d a e t d a e t d a e t d a e t 4 4 4 4 4 4 4 2 5 u u l u l u l u l u l u l u l u l u l a u l u s d s a d s d s d s d s d s d s d s d s d K KK KK KK . 3 0 1 m e i l t mit mit mit mit mit mit mit mit mit mit mit e a b e a e a e a e a e a e a e a e a e S a b a b a b a b a b a b a b a b a b a C S 3 C S 3 C S 3 C S 3 C S 3 C S 3 C 9 1 3 0 9 b S s- s a n - s n - s n - s n - s n - s n - s n - s n - s n - s - n n n n n n n n n n mmmmmmm 7 4 1 T U U U U U U U U Un Un U y Dy Dy Dy Dy Dy Dy Dy Dy D y D a P a P a P a P a P a P a P / 1 B D 0 5 O W-2 1 0 5- 8 7 . 5 9 . 6 8 . † 7 † † 7 2 5 . 4 . 8 . 9 . $ 4 ± ± ± 5 7 2. 4 . 4 6 9 8 . 1 . 6 . 6 6 4 3 3 1 . 7 . † . 8 . 0 1 3 6 5. 1 9 . . 8 6 8 2 7 9 2 7 1 5 9 2 8 3 3 3 1 5 4 6 3 0 1 ± ± 3 1 1 1 - ± I 1 ± ± ± ± ± L ± 1 ) 5 5 ± ± ± ± e . . 4 9 . ± 2 8 ± . 3 4 . 3 . 2 . 1 3 . 3 9 . 5 2 . ± 6 7 . 1 . 1 . 3 . n 4 3 o 5 2 3 8 6 8 3 4 l 1 5 1 3 1 1 . 3 1 4 9 4 3 4 5 3 3 8 1 5 5 5 6 a 6 1 2 3 3 3 3 n o i 9 . 8 t . a l ) u s n * * 8 0 2 moi t 6 1 2 1 1 . 1 * 5 . 8 . 2 . 8 . ± it i 2 . ± ± s 1 3 . 8 . t d . . . . 8 . s n o 6 4 2 . 5 . * - 0 0 1 0 0 0 5 3 0 ± 0 3 5 . 7 5 0 7 4 9 1 5 5 ± 4 L ± 0 . ± ± ± ± ± ± 8 ± ± ± ± ± 3 9 7 n i a c I 0 0 1 1 3 3 5 . . 6 6 ± 2 1 5 . 5 . g d . a e t ) ) 1 . 0 . 0 . 0 3 1 0 2 . 0 . 6 8 . . 1 5 . 6 8 3 6 0 6 n a l n o n 2 1 8 3 4 5 oi t u i a m s o l it s i s s u s e - r e g r 3 . 3 0 . 0 0 m i n u e g R e R * * 5 . 2 . 2 . 6 . ± ± ± t s t 3 h s c t n i i t s c R i t O 5 . 5 . 6 s 5 < 1 2 0 6 4 0 < 0 < 0 6 1 8 4 3 5 6 1 5 . 5 0 . 0 . 0 i wa t g i a g i O o g o s - R i L t I O0 . O 0 0 . 0 0 . 0 0 . 0 0 . 0 ± R 3 . O0 . R O ± 1 O 0 O 0 ± ± 2 ± . 1 ± . 5 ± . 3 . n n L L n 0 6 . 3 4 5 6 e o ( ( i 9 3 2 4 2 3 2 2 mt i a t a e e R o e l v r v p 1 2 6 r u r Od 8 2 t u u m C C O e ri 1 . 3 g its d r d r r a h t 1 . 2 1 . 1 nir 2 ± a g a a n s t e h ) $ . 7 . 6 . 2 . i d n d 5 ± ± n n i t s 3r 5. 4 2 8 8 3 4 . 1 . 6 . p mr a a t a c S t o p a s o n 4- < R 9 0 9 9 8 0 0 0 9 8 1 5 1 5 7 ± 2 3 1 ± 1 3 2 3 o p ( m e S e r t n o L I O. 0 0 . 0 0 . 0 5 . 0 3 . 0 2 . 0 1 . 0 0 . 0 5 . 0 8 . 0 ± 3 ± 8 ± 1 o h t h t e h i o D ( O 3 . . 2 2 0 . 9 6 0 c ( 0 e t 0 1 v w o p a s C 2 2 5 0 9 1 9 0 2 3 2 0 0 o o l s a t a 1 2 M . 0 b A e t n d M B µ O S 0 0 3 < 0 . 0 e B g e i g o p o w P t n M O 0 M $ p 0 M < n . 0 µ D; p a n _ 0 _ l 1 0 ; R a a f R t a f i o s tl M MMM MM µ µ µ M µ µ S 3 M M MM MM µ µ 8 1 _ o rt 0 0 . 1 0 o f d e u t ot e l g g a r s D µ 0 µ µ 3 . 1 . 3 0 . 1 0 . 0 0 M . µ D µ _ 0 µ µ 3 . 1 . e e R I e 1 _ 3 _ 1 _ 0 _ 0 _ 0 _ 0 _ 0 _ 0 l o 1 _ 3 _ 1 _ 0 0 d e n n l o o 0 0 0 u u . O Oni s v a e l n p 8 8 8 8 8 8 8 8 1 rt 8 8 8 _ 8 _ d d d _ e l n 8 u o r p o c b t < p 0 i k ma n ma n e * < u n u n d u n d u n d d d u n u n u n u o r o c d d n d n d n d n d n o si v * † p o t y S o p o p o p o p o p o p o p o p o b t n r a u o u u u u p o p o o o C r l C o * S ; 1 † † 0 ; C m 1 . d o m C o m C o m a C o m C o m C o m C o m C o s e i C r v l d n p p p a mmmmm C o S t o o o o o 0 . 0 < 0 a e S C C C C C 0 . t a u n d d d d d d d 4 K 4 S K 4 p 0 K * < *† † p D i d t e a n t e t t o c n a l a e l t a e t a e t a e t a e t a e t d a e t d a e t d e t d e t 2 u l u l u l u l u l u l u l a l a l a l s d s d s d s d s d . 3 0 C S 3 C S m 3 C ; 3 1 ; 0 . 1 0 . > < n il r a e D 5 1 u u u u u mi m a it m s it mmmmmmmmme a e a e a e a e 9 1 s it s it s it s it s it it it it it b a b a b a b a b a 0 9 a mm0 0 R OR Od P a P a P < p < n d l e l t S -n -n -n -n -n - s n - s n - s n - s- s - n n n n n 7 4 1 * † p O O Uo B b a n n n y y y y y T U U U U U U U U U U U D D D D D / 1 B D 5 0 5 O W-2 1 0 5 3 - . 2 5 4 0 4 . . 0 . 2 8. 0 $8$ 6 . * 4 1 * 7 8 2 . . 3 7 . 4 1 . 1 . 9 0 8 . 3. 1 . 6 2 3 5 4 3 0 ± 7 ± ± 9 . ± 1 . 6 2 4 5 1 2 6 4 7 7 4 3 9 7 ± ± 1 2 7 A 7 < < 1 R R 0 ± 0 4 . 0 2 0 . 1 . 3 6 . ± 2 6 1 5 0 7 . 1 . 8 5 . ± 2 ± ± 3 ± 9 4 . ± 9 . 5 . 7 . ± 4 . ± ± 6 4 - . L OO I O O1 . 0 0 0 0 6 7 3 6 3 1 6 5 3 9 . 3 6 3 6 6 . 4 6 6 . 2 0 1 4 9 3 9 4 2 7 ) e 3 4 6 4 0 3 1 4 5 9 0 3 5 3 5 6 3 5 3 3 6 3 n o l a n o i t a ) 0 7 7 . † 5 2 4 . 0 * † 0 7. 6 * * * 7 8 † 8 * 7 . * 2 . 6 . . 2 5 1 0 0 9 . 6 . 5 8 l . u s n 4 m i oi t i 3 1 < R < R < R < R 4 8 ± 2 9 5 0 . 8 . 7 4 5 3 1 1 7 4 0 1 t s d - O 2 . 3 . 8. ± ± ± 1 0 0 3 6 3 9 . 4 . ± ± ± ± ± 1 ± 6 ± ± ± 2 1 . 2 . ± t 9 ± 9 s n ni o L c I OOO O O O O 0 0 65 . 1 2 2 7 6 2 5 1 2 4 . 7 3 . 1 3 . . 3 . 5 0 3 7 2 1 7 . 1 1 1 9 3 4 4 1 . 5 4 5 5 . 6 9 7 1 a 5 g d a e t n a ) l n ) o i
Figure imgf000288_0001
t u o i n o a m l i s t s i s s e r s e r 3. 5 6 * † u 5 . 0 . 3 * † - 7 . 1 2 1 1 2 m i n g t s u e e t R 0 c R c R 7 p 0 0 0 0 1 . 0 0 2 2 1 2 . 0 0 . 0 . 0 . . . 0 s n i i O 2 ± 0 ± ± ± ± ± 4 ± ± 7 3 . 5 5 ± ± ± 0 0 1 ± ± ± 0 1 0 . ± ± 0 0 ± ± ± hti i a t si tsi O 1 - 1 . . 0 0 1 . 0 1 . 1 0 1 . . 0 7 . 2 . 1 2 . 6 . . 0 0 1 . 1 0 . 0 0 2 . 1 0 . 0 2 . 1 2 0 . . 0 w t g a g o g s i L L o t I 0 32 7 2 4 2 0 2 8 8 0 n 2 e n mo t i ( L e ( n e R i o 7 a t a v e l r v r O p 8 2 rt u u C u d C O ri 1. 4 6 . 9 * * 7 g mi n ts d e r 7 3 . 3 8 1 6 4 * 7 . . 8 1 3 ir g a d r r a a h t n d d s t e ) n h t 3 < 9 . 7 . 2 ± 5 ± ± 0 1 8 . 0 3 . 0 6 . 0 6 . 0 8 . 6 . 6 . 8 . 9 . . a p ir n a n a i o s a r o 0 1 7 R 0 0 0 ± . 6 5 4 ± ± ± ± ± 0 4 1 2 1 1 4 . 5 . 5 ± ± ± ± ± ± ± m o a p t S t S pr s t n - 1 o L I . 0 O± 3 4 . ± 2 3 . 5 . 7 . 3 . 3 . 1 7 . 6 . 1 . 5 . 5 . c ( m o e h . 1 5 9 . t e h t e h n i O o D ( 1 . 2 3 5 2 9 7 9 . 8 0 1 1 0 1 1 3 2 2 2 1 1 c ( e t o p s 2 2 2 1 1 1 0 2 0 0 0 1 0 0 v o w s a t C . b o l e a a M 0 0 0 A B t n i d o B 0 . e e o P M µ MM µ µ O S O < p w n 3 MM MMMMM µ S $ p 0 g g t M µ µ µ µ 3 M; < n i p a n a R a R t a f o s t M l M M µ M µ µ 3 0 . 1 0 0 . 0 0 0 M . D µ 0 µ _ l 0 1 µ M 3 µ 3 1 0 M D1 f f d e u µ MM 3 1 3 . 0 1 . 0 0 . 0 0 . 0 0 . µ _ l 0 0 ; 1 o o e l g a s e D I 0 µ µ 3 . 1 . 0 . _ _ _ 0 _ o _ _ _ _ 0 0 o 0 0 t t g r e R e 1 3 1 0 0 0 8 8 8 1 rt n 8 8 8 8 _ 8 _ 8 _ 8 _ 8 1 _ rt . n 0 0 0 u Ou Oni l _ _ _ _ _ _ n s v a e p 8 8 8 8 8 8 d d d e l o d d d d d d d d e l o u n o u n u o r < . n i d d d d d d p o p o p o c b t n u n u n u n u n u n u n u n u o r o c t p 0 * < k m ot a S n u n u n u n u n u n u a n e o o o o o o o o v p p p p p p p p b a n e * v * ; † †p † y o o o o o o C p p p p p p mo mmsi C o C o C r l m C o S o m C o m C o m C o m C o m C o m C o m C o si C r l C o S 1 0 ; mmmmmm 0. 1 . d o o o o o o 0 0 < 0 C C C C C C . a t e u s p 0 a < D n it t d e t d e t d e t d e t d e d e d s a d s d s d s d 4 e a K 4 K 4 K4 K 4 K4 K 4 4 4 4 * * † p d e a n o n a a l a l a l a l t a l t a l 2 . 3 b e a e a e a e S S S S S S K S K S K S K S ; † a b n a b a b a b C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 1 ; 0 . 1 n i t 0 > < l r a c e D 5 l 1 u u u u u u u 0 mmmmmmm 9 1 i it it it it it it 0 9 y n y n y n a y n y mmmmmmmmmm0 . 0 R OR Od n d l e l t S s- s n - s n - s- s- s - 7 4 1 D D D D D a P a P a P a P a P a P a P a P a P a P < p < * † p O O Uo B b a n n n n T U U U U U U / 1 B D 5 0 5 O W-2 1 0 5 - 3 . 7 . * * * 5 . 9 5 . 4 2 . 1 . 3 . 6 7 3 6 . 9 * 4 . * † 3 † . 8 . * 7 3 1 5 6 5 † † 4 1 6 0 0 0 0 8 . 3 ± 3 1 0 1 6 2 3 4 3 4 2 7 ± 1 1 8 3 3 8 2 . 0 0 . 0 . 0 . 0 . 1 . 1 2 . 2 ± 0 . 0 0 3 3 . 4 . 0 . 3 0 . 0 ± 1 1 1 . ± ± ± ± ± ± ± 1 4 . 6 2 . 6 3 . 7 4 3 2 ± ± ± 5 . 0 ± ± ± ± ± ± 8 9 1 7 3 5 . 9 ± 9 . 7 8 0 . . . 1 5 0 0 . 4 9 9 1 . 9 6 . 8 7 . 0 . 0 . 0 . 1 . 2 . 3 3 . 1 6 . 2 ) 1 4 6 7 5 7 6 7 6 5 4 1 7 6 e n o l a n o 1 $ * 9 i . 7 . 3 4 . 7 6 . 4 . 1 . 3 . 6 . 8 . t a l ) s 4 5 . . 6 3 8 4 3 9 6 2 0 2 7 2 4 0 6 1 0 7 2 8 9 4 . 6 3 . 4 7 4 9 u n 0 . 0 . . . 4 . moi t ± 0 5 0 8 . 7 . 3 . 0 6 2 ± ± ± ± 2 ± ± ± ± 5 ± 0 6 5 0 0 0 0 2 . 1 . 6 . ± ± 3 . ± ± ± 1 it s i d 8 . 0 0 0 ± ± 2 1 6 . 5 7 . 3 . 6 1 0 0 8 . 8 6 . 7 6 8 . 8 8 . 3 5 . 8 0 0 0 3 . 5 . 1 7 . 9 . 6 . ± 2 t s n o 2 0 4 1 2 3 3 5 5 7 4 5 0 0 0 0 2 n i c 1 8 1 8 1 2 2 2 2 2 0 2 6 1 2 a g d a e t n a l o i t u a m l it 1. 1 . 3 . 9 . 9 . 5 8 . 6 . 9 . 8 . 4 . 1 . 4 . 1 u s- . 1 . 1 . 3 . 1 . 1 1 2 m n 0 0 0 0 ± ± ± 0 0 7 1 0 6 0 7 1 0 6 0 0 ± 0 0 0 0 0 . 0 . 0 . 0 i t s u t ± ± ± ± ± ± ± ± ± ± ± ± s 1. 1 0 . 1 0 . 1 0 . 0 1 . 3 7 . ± 0 . 0 8 7 1 . 5 4 . 1 . 2 5 . 6 . 3 4 . 1 . 1 . ± 2 ± 1 ± 1 ± 3 ± 3 ± 3 ± 2 ± 3 hti n i a 1 8 0 1 . 8 6 2 1 1 . 0 6 1 0 0 . 0 . 0 . 0 . 0 . 0 . 0 . 0 . 0 w t g n a e n mo t i t a 8 l 8 2 * † 7 * † a † e rt u m 6. * 1 . 4 3 0 5 . 3 9 . 4 . 4 . 9 . * 6 . 8 . † g its 1 4 . 6 3 . 0 4 8 . . 5 * 9 6 . 2 6 1 2 2 7 1 7 8 9 1 4 6 9 9 1 5 0 2 2 9 3 1 * * 2 . * 5 . * 3 . 8 . 2 7 . 8 5 . 0 7 . 6 9 . 6 . ni 9 r a g ni ± ± 1 ± 3 1 ± ± ± ± ± 2 1 0 8 0 4 2 ± ± ± ± 7 p r a 7 9 . . ± 6 3 . 1 1 . 7 5 9 7 .
Figure imgf000289_0001
7 . 9 6 . ± ± ± 4 7 9 5 . 0 ± ± ± 6 . 4 . . 7 . 8 2 . 0 3 . 2 1 ± 5 3 1 o c 3 m 7 4 4 5 5 5 3 5 3 0 5 9 2 4 4 4 5 o 13 6 2 8 0 9 9 8 6 9 8 3 4 5 1 c 1 5 0 ( 1 0 0 0 1 0 0 . 0 0 0 O O O < 0 . MM S MMM S MMM S p 0 µ µ 1 3 M M M µ M µ µ µ 3 MM MM µ µ µ 3 M $ ; < 0 p . 0 0 0 M . µ D µ MM µ 0 µ µ 3 . 1 . 3 0 . 1 0 0 0 M µ D µ M µ M µ µ µ 3 1 3 0 1 0 0 0 M µ D1 0 ; _ 0 _ 8 _ 0 l 8 1 d _ or 1 _ 3 _ 1 _ 0 _ 0 _ 0 . _ 0 . 0 0 _ l 0 . . . . . _ o 1 3 1 0 0 0 0 0 0 l o 0 0 1 0 e t n 8 8 8 8 8 8 _ 8 _ 8 1 _ r e t _ _ _ _ _ _ _ _ 1 r n 8 8 8 8 8 8 8 8 _ e t . n 0 0 0 n d . u n l o o c d n d n d n d n d n d n d n d n l o o c d n d n d n d n d n d n d n d n l o o < p 0 o u p o r p o b t d n r a u o u p o u p o u p o u p o u p o u p o u p o r p o b t n u o u p o u p o u p o u p o u p o u p o u o r o c b t n * * < † p mo ma o s e i r v l d n a mmmmmmmmas e i v p p l mmmmmmmmas e i v l * ; C S S C C C C C C C C C S C C C C C C C C C S 1 † † ; C C o t o o o o o o o o r o o o o o o o o o r o 0 0 . 1 0 d t d a e 0 0 . e l t d a e u l t d a e u l t d a e u l t < 0 a u l u s d s a d s a d s a d s a d s a d s a d s a d s a d s a d 4 a K 4 p < K4 K 4 K4 K 4 K4 4 4 4 * * † p 2 . 3 i S S K K K K ; † ; 0 mt m s i - t m s it mit mit e b e e e e e e e e e S S S S S S S S a b a b a b a b b b b b b C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 1 0 9 . 1 0 1 0 9 n - s n - s n - s n -n n y n y n y n a y n a n a n a n a n a n mmmmmmmmmm0 . 0 7 4 1 U U U U U D D D Dy Dy Dy Dy Dy Dy D a P a P a P a P a P a P a P a P a P a P < p < * / † p 1 B D OOR > Out of Range Above the Standard Curve (Logistic Regression) OOR < Out of Range Below the Standard Curve (Logistic Regression) Underlined Data single data point as other points are OOR Bold Data average of two data points as the third point is OOR Table 15 continued. Cytokine Results in PBMCs (Donor 3) Stimulant Sample ID IL-23 TNFα Un-stimulated Compound 8_10 µM 5.11 0.2 ± 0.1 Un-stimulated Compound 8_3 µM OOR< 0.3 ± 0 Un-stimulated Compound 8_1 µM OOR< 2 ± 2.3 Un-stimulated Compound 8_0.3 µM OOR< 0.7 ± 0.2 Un-stimulated Compound 8_0.1 µM OOR< 1 ± 0.1 Un-stimulated Compound 8_0.03 µM 2.43 2 ± 1 Un-stimulated Compound 8_0.01 µM 21.25 43.2 ± 46.6 Un-stimulated Compound 8_0.003 µM 2.43 5.5 ± 2.4 Un-stimulated Crisaborole_10 µM OOR< 0.4 ± 0.2 Un-stimulated Solvent control_DMSO OOR< 4 ± 1.6 Un-stimulated Standard OOR< 19.6 ± 10.1 Dynabeads Compound 8_10 µM 10.49** 24.5 ± 30.3 Dynabeads Compound 8_3 µM 503.1 ± 107.1 1950.4 ± 155.5 Dynabeads Compound 8_1 µM 330.4 ± 99.3 2268.8 ± 303.9 Dynabeads Compound 8_0.3 µM 546.9 ± 160.2 1978.9 ± 215.5 Dynabeads Compound 8_0.1 µM 391.7 ± 76 2257.4 ± 171.3 Dynabeads Compound 8_0.03 µM 349.6 ± 83 2707.6 ± 422.2 Dynabeads Compound 8_0.01 µM 410.3 ± 136.2 2943.1 ± 431.5 Dynabeads Compound 8_0.003 µM 517.4 ± 71.8 2291.9 ± 271 Dynabeads Crisaborole_10 µM 6.50** 81.6 ± 28.3 Dynabeads Solvent control_DMSO 358.1 ± 40.6†† 3481.4 ± 1781.1 Pam3CSK4 Compound 8_10 µM 16.8 ± 6.8 0.6 ± 0.4$ Pam3CSK4 Compound 8_3 µM 11.4 ± 1.6 0.6 ± 0.3$ Pam3CSK4 Compound 8_1 µM 15.90 4.6 ± 5.8$ Pam3CSK4 Compound 8_0.3 µM 7.80 4.8 ± 0.5$ Pam3CSK4 Compound 8_0.1 µM 14.1 ± 6.2 21.9 ± 3$ Pam3CSK4 Compound 8_0.03 µM 29.9 ± 29.2 59.4 ± 13.7 Pam3CSK4 Compound 8_0.01 µM 34.3 ± 29.9 76.4 ± 4.6 Pam3CSK4 Compound 8_0.003 µM 28.2 ± 29.1 78.9 ± 2.4 Pam3CSK4 Crisaborole_10 µM 22.1 ± 10.9 4 ± 0.5$ Pam3CSK4 Solvent control_DMSO 9.6 ± 5.6 81.7 ± 1.4 *p< 0.01; **p<0.001; ***p< 0.0001; $p< 0.00001 (comparing treatment with stimulation against stimulation alone) †p< 0.01; ††p<0.001; †††p< 0.0001; p< 0.00001 (comparing stimulation against un-stimulated conditions) DB1/ 147901903.2 289 OOR > Out of Range Above the Standard Curve (Logistic Regression) OOR < Out of Range Below the Standard Curve (Logistic Regression) Underlined Data single data point as other points are OOR Bold Data average of two data points as the third point is OOR Table 16. Cell Viability Post Treatment (Donor 1) Stimulant Sample ID Viable % Parent Viable Events/μL(V) Unstimulated standard 99.1% ± 0.2% 790 ± 21.2 Unstimulated solvent control 99.1% ± 0.1% 867.5 ± 13.2 Unstimulated Crisaborole_10 µM 99% ± 0.1% 897.5 ± 3.8 Unstimulated Compound 8_10 µM 95.7% ± 0.4% 762.1 ± 26.9 Unstimulated Compound 8_3 µM 96.8% ± 0.4% 804.3 ± 15.7 Unstimulated Compound 8_1 µM 97% ± 0.1% 799.3 ± 6.3 Unstimulated Compound 8_0.3 µM 98.6% ± 0.1% 823.4 ± 1.1 Unstimulated Compound 8_0.1 µM 99% ± 0.2% 840.3 ± 31.9 Unstimulated Compound 8_0.03 µM 99.1% ± 0.1% 848.5 ± 23.6 Unstimulated Compound 8_0.01 µM 99.1% ± 0.1% 838 ± 14 Unstimulated Compound 8_0.003 µM 99.2% ± 0.2% 843.7 ± 18.7 Dynabeads solvent control 85.7% ± 0.2% 745.7 ± 27.8 Dynabeads Crisaborole_10 µM 95.4% ± 0.4% 888.3 ± 39.3 Dynabeads Compound 8_10 µM 96.6% ± 0.9% 775.3 ± 19.6 Dynabeads Compound 8_3 µM 90.6% ± 2.5% 816 ± 46.8 Dynabeads Compound 8_1 µM 85.4% ± 0.7% 721.3 ± 39.6 Dynabeads Compound 8_0.3 µM 85.9% ± 0.6% 749.9 ± 27.9 Dynabeads Compound 8_0.1 µM 85.9% ± 0.4% 743.5 ± 8.5 Dynabeads Compound 8_0.03 µM 86% ± 0.2% 752.5 ± 27.1 Dynabeads Compound 8_0.01 µM 84.9% ± 0% 724.4 ± 22.9 Dynabeads Compound 8_0.003 µM 85.9% ± 0.3% 737.5 ± 20.8 Pam3CSG4 solvent control 99.3% ± 0.1% 854.9 ± 18 Pam3CSG4 Crisaborole_10 µM 98.5% ± 0.1% 847.5 ± 25.4 Pam3CSG4 Compound 8_10 µM 96.1% ± 0.7% 718.8 ± 34.1 Pam3CSG4 Compound 8_3 µM 96.8% ± 0.1% 761.7 ± 11.8 Pam3CSG4 Compound 8_1 µM 97.1% ± 0.3% 773.5 ± 21 Pam3CSG4 Compound 8_0.3 µM 98.8% ± 0.1% 809.3 ± 34.3 Pam3CSG4 Compound 8_0.1 µM 98.9% ± 0.1% 801 ± 21.5 Pam3CSG4 Compound 8_0.03 µM 99% ± 0.1% 825.7 ± 16 Pam3CSG4 Compound 8_0.01 µM 99.1% ± 0.1% 852 ± 8.9 Pam3CSG4 Compound 8_0.003 µM 99.3% ± 0.1% 826.7 ± 17.2 Table 17. Cell Viability Post Treatment (Donor 2) Stimulant Sample ID Viable % Parent Viable Events/μL(V) Unstimulated standard 98.2% ± 0.4% 646.1 ± 21.4 Unstimulated solvent control 98.3% ± 0.1% 658.3 ± 15.7 DB1/ 147901903.2 290 Unstimulated Crisaborole_10 µM 97.5% ± 0% 683.5 ± 2.2 Unstimulated Compound 8_10 µM 93.3% ± 0.3% 593.1 ± 17.4 Unstimulated Compound 8_3 µM 93.7% ± 0.1% 618.7 ± 8 Unstimulated Compound 8_1 µM 94.2% ± 0.2% 639.8 ± 16.9 Unstimulated Compound 8_0.3 µM 95.6% ± 1.2% 635.1 ± 20.7 Unstimulated Compound 8_0.1 µM 96.6% ± 0.4% 641.5 ± 25.9 Unstimulated Compound 8_0.03 µM 98.2% ± 0.4% 655.1 ± 4.6 Unstimulated Compound 8_0.01 µM 98.1% ± 0.7% 668 ± 21.4 Unstimulated Compound 8_0.003 µM 98.7% ± 0.1% 670.6 ± 8.4 Dynabeads solvent control 89% ± 0.4% 581.8 ± 0.7 Dynabeads Crisaborole_10 µM 96.6% ± 0.1% 613.3 ± 11.2 Dynabeads Compound 8_10 µM 95.9% ± 0.7% 581.2 ± 12.4 Dynabeads Compound 8_3 µM 93.3% ± 0.9% 654 ± 15.5 Dynabeads Compound 8_1 µM 88.9% ± 0.3% 604.6 ± 5.9 Dynabeads Compound 8_0.3 µM 88.4% ± 0.1% 596.9 ± 15 Dynabeads Compound 8_0.1 µM 88.8% ± 0.4% 600.6 ± 15.4 Dynabeads Compound 8_0.03 µM 88.4% ± 1% 591.7 ± 16.2 Dynabeads Compound 8_0.01 µM 89% ± 0.2% 600.8 ± 13.9 Dynabeads Compound 8_0.003 µM 87.5% ± 0.2% 570.8 ± 6.8 Pam3CSG4 solvent control 99% ± 0.2% 664.3 ± 18.7 Pam3CSG4 Crisaborole_10 µM 98.4% ± 0.1% 672.8 ± 11 Pam3CSG4 Compound 8_10 µM 92.1% ± 0.7% 576.5 ± 16.8 Pam3CSG4 Compound 8_3 µM 93.5% ± 0.5% 601.6 ± 13 Pam3CSG4 Compound 8_1 µM 95.1% ± 0.2% 600.4 ± 15.8 Pam3CSG4 Compound 8_0.3 µM 98.5% ± 0.1% 624 ± 3.1 Pam3CSG4 Compound 8_0.1 µM 99.2% ± 0.2% 640.9 ± 7.5 Pam3CSG4 Compound 8_0.03 µM 98.7% ± 0.2% 656.6 ± 5.4 Pam3CSG4 Compound 8_0.01 µM 98.9% ± 0.1% 646.5 ± 3.3 Pam3CSG4 Compound 8_0.003 µM 99% ± 0.2% 656.8 ± 4.9 Table 18. Cell Viability Post Treatment (Donor 3) Stimulant Sample ID Viable % Parent Viable Events/μL(V) Unstimulated standard 98.6% ± 0.4% 753.9 ± 39.5 Unstimulated solvent control 98.7% ± 0% 755.2 ± 9 Unstimulated Crisaborole_10 µM 97.3% ± 0% 764.8 ± 14.4 Unstimulated Compound 8_10 µM 94.4% ± 0.3% 692.1 ± 23.8 Unstimulated Compound 8_3 µM 94.6% ± 0.1% 704.2 ± 10.2 Unstimulated Compound 8_1 µM 95.7% ± 1% 716.6 ± 4.1 Unstimulated Compound 8_0.3 µM 96.7% ± 1.3% 718.8 ± 22.9 Unstimulated Compound 8_0.1 µM 97.8% ± 0.6% 725.4 ± 24.4 Unstimulated Compound 8_0.03 µM 98.5% ± 0.3% 745.5 ± 35.3 Unstimulated Compound 8_0.01 µM 98.8% ± 0.2% 756.4 ± 46.6 Unstimulated Compound 8_0.003 µM 98.8% ± 0.1% 755.7 ± 7.3 Dynabeads solvent control 89.6% ± 0.6% 752.8 ± 27.5 DB1/ 147901903.2 291 Dynabeads Crisaborole_10 µM 95.9% ± 0.6% 763.4 ± 17.2 Dynabeads Compound 8_10 µM 96.8% ± 1.1% 680.5 ± 4.8 Dynabeads Compound 8_3 µM 93% ± 1.8% 781.6 ± 12.3 Dynabeads Compound 8_1 µM 90.5% ± 0.7% 773 ± 10.8 Dynabeads Compound 8_0.3 µM 90.6% ± 0.3% 791.5 ± 24.3 Dynabeads Compound 8_0.1 µM 89.9% ± 0.2% 778.5 ± 10.4 Dynabeads Compound 8_0.03 µM 89.8% ± 0.3% 798.2 ± 21.1 Dynabeads Compound 8_0.01 µM 89% ± 0.3% 772.9 ± 8.6 Dynabeads Compound 8_0.003 µM 89.9% ± 0.3% 769.7 ± 16.3 Pam3CSG4 solvent control 99.1% ± 0.2% 762.4 ± 8.7 Pam3CSG4 Crisaborole_10 µM 97.9% ± 0.1% 765.9 ± 20.4 Pam3CSG4 Compound 8_10 µM 94.1% ± 0.2% 675.2 ± 42.7 Pam3CSG4 Compound 8_3 µM 94.6% ± 0.3% 691.9 ± 25.2 Pam3CSG4 Compound 8_1 µM 96.4% ± 1.3% 715.4 ± 29 Pam3CSG4 Compound 8_0.3 µM 97.3% ± 0.4% 715.8 ± 28.4 Pam3CSG4 Compound 8_0.1 µM 98.7% ± 0.1% 724.9 ± 22.1 Pam3CSG4 Compound 8_0.03 µM 99% ± 0% 741.9 ± 8.5 Pam3CSG4 Compound 8_0.01 µM 99% ± 0.1% 748.3 ± 20.9 Pam3CSG4 Compound 8_0.003 µM 99.1% ± 0.1% 750.9 ± 13.5 Conclusions This experiment assessed the effect of Compound 8 on cytokine secretion in PBMCs from three normal donors, which were pre-treated with CD3-CD28 Dynabeads (adaptive immune response stimulator) or Pam3CSK4, a TLR agonist stimulating innate immune responses. Treatment with Dynabeads or Pam3CSK4 induced a number of cytokines in all donors. Variation was seen between donors, but this was an expected finding (Römer et al, 2001). When Compound 8 was added to the PBMCs stimulated with Dynabeads, there was a significant reduction in multiple cytokines and this varied between donors. However, there was a trend whereby if the Dynabeads induced cytokine secretion in a given donor, Compound 8 at 10 µM reduced this induction in all cases and additionally at 3 and 1 µM for a limited range of cytokines (IL-1 β in two of three donors and IL-6 in all donors). Crisaborole reduced the amount with one exception of IL-8 where there was no reduction in any donor. When Compound 8 was added to the PBMCs stimulated with Pam3CSK4, there was a significant reduction in multiple cytokines and again this varied between donors. In some cases, where Pam3CSK4 alone did not induce a statistically significant induction as compared to the solvent control, co-culture of Pam3CSK4 and Compound 8 significantly reduced the cytokine induction. For Donor 1, Compound 8 reduced IL-8 and IL-10 from 10 – 0.3 µM and TNFα from 10 – 1 µM. For Donor DB1/ 147901903.2 292 2, Compound 8 reduced IL-6 from 10 – 0.3 µM, IL-8 from 10 – 1 µM, IL-10 and TNFα from 10 – 0.1 µM. For Donor 3, Compound 8 reduced IL-6 and TNFα from 10 – 0.1 µM, IL-8 and IL-10 from 10 – 0.3 µM and IL-17 at 10 µM. Cell viability was never compromised in any of the treatment conditions, therefore changes in cytokine levels are due to compound activity and not cell death. There was no consistent trend in cytokine inhibition across donors with either stimulation below 1 µM Compound 8. Reference Römer, Paula S. et al., “Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412,” Blood, 2011, Vol.18, No.2 It is noted that terms like “preferably,” “commonly,” and “typically” are not used herein to limit the scope of the claimed disclosure or to imply that certain features are critical, essential, or even important to the structure or function of the claimed disclosure. Rather, these terms are merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the present disclosure. The various methods and techniques described above provide a number of ways to carry out the disclosure. Of course, it is to be understood that not necessarily all objectives or advantages described can be achieved in accordance with any particular embodiment described herein. Thus, for example, those skilled in the art will recognize that the methods can be performed in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objectives or advantages as taught or suggested herein. A variety of alternatives are mentioned herein. It is to be understood that some preferred embodiments specifically include one, another, or several features, while others specifically exclude one, another, or several features, while still others mitigate a particular feature by inclusion of one, another, or several advantageous features. Furthermore, the skilled artisan will recognize the applicability of various features from different embodiments. Similarly, the various elements, features and steps discussed above, as well as other known equivalents for each such element, feature or step, can be employed in various combinations by one of ordinary skill in this art to perform methods in accordance with the principles described herein. Among the various elements, features, and steps some will be specifically included and others specifically excluded in diverse embodiments. DB1/ 147901903.2 293 Although the application has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the embodiments of the disclosure extend beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and modifications and equivalents thereof. In some embodiments, the numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the application are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. In some embodiments, the terms “a” and “an” and “the” and similar references used in the context of describing a particular embodiment of the application (especially in the context of certain of the following claims) can be construed to cover both the singular and the plural. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (for example, “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the application and does not pose a limitation on the scope of the application otherwise claimed. As used in the disclosure or claims, “another” means at least a second or more, unless otherwise specified. As used in the disclosure, the phrases “such as,” “for example,” and “e.g.” mean “for example, but not limited to” in that the list following the term (“such as,” “for example,” or “e.g.”) provides some examples but the list is not necessarily a fully inclusive list. The word “comprising” means that the items following the word “comprising” may include additional unrecited elements or steps; that is, DB1/ 147901903.2 294 “comprising” does not exclude additional unrecited steps or elements. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the application. In certain instances, sequences disclosed herein are included in publicly available databases, such as GENBANK® and SWISSPROT. Unless otherwise indicated or apparent the references to such publicly available databases are references to the most recent version of the database as of the filing date of this Application. Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter. As used herein, the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method. Preferred embodiments of this application are described herein. Variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. It is contemplated that skilled artisans can employ such variations as appropriate, and the application can be practiced otherwise than specifically described herein. Accordingly, many embodiments of this application include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the application unless otherwise indicated herein or otherwise clearly contradicted by context. DB1/ 147901903.2 295 Appendix A Table 4. List of NFκB target genes from FIG.4B NFkB gene list A4 CTSL1 IL12A PSMB9 ABCA1 CXCL1 IL12B PSME1 ABCB1 CXCL1 IL13 PSME2 ABCB4 CXCL1 IL15 PTAFR ABCB9 CXCL1 IL17 PTEN ABCC6 CXCL10 IL1A PTGDS ABCG5 CXCL10 IL1B PTGES ABCG8 CXCL11 IL1RN PTGIS ADAM19 CXCL3 IL2 PTGS2 ADH1A CXCL3 IL23A PTHLH ADORA1 CXCL5 IL27 PTPN1 tabADORA2A CXCL5 IL2RA PTPN13 ADRA2B CXCL5 IL6 PTS AFP CXCL6 IL8 PTX3 AGER CXCL9 IL8RA PYCARD AGT CYP19A1 IL8RB RAG1 AHCTF1 CYP27B1 IL9 RAG2 AICDA CYP2C11 INHBA RBBP4 AKR1C1 CYP2E1 IRF1 Rdh1 ALOX12 CYP7B1 IRF2 Rdh7 ALOX5 DCTN4 IRF4 REL AMACR DEFB2 IRF7 RELB AMH DIO2 JMJD3 REV3L ANGPT1 DMP1 JUNB RIPK2 APOBEC2 DNASE1L2 KC S100A10 APOC3 DPYD KCNK5 S100A4 APOD DUSP1 KCNN2 S100A6 APOE E2F3 KISS1 SAA1 AQP4 EBI3 KITLG SAA2 AR EDN1 KLF10 SAA3 ARFRP1 EGFR KLK3 SAT1 ART1 EGR1 KLRA1 SCNN1A ASPH ELF3 KRT15 SDC4 ASS1 ENG KRT3 SELE ATP1A2 ENO2 KRT5 SELP B2M EPHA1 KRT6B SELS BACE1 EPO LAMB2 SENP2 BAX ERBB2 LBP SERPINA1 BCL2 ERVWE1 LCN2 SERPINA2 BCL2A1 F11R LCN2 SERPINA3 BCL2L1 F3 LEF1 SERPINB1 DB1/ 147901903.2 296 NFkB gene list BCL2L11 F8 LGALS3 SERPINE1, PAI-1 BCL3 FABP6 LIPG SERPINE2 BDKRB1 FAM148A LTA SH3BGRL BDKRB1 FAS LTA SKALP, PI3 BDNF FASLG LTB SKP2 BGN FCER2 LTF SLC11A2 BLIMP1 /PRDM1 FCER2/CD23 LYZ SLC16A1 BLNK FCGRT MADCAM1 SLC3A2 BLR1 FGF8 MAP4K1 SLC6A6 BMI1 FN1 MBP Slfn2 BMP2 FOS MDK SNAI1 BMP4 FSTL3 MMP1 SOD1 BNIP3 FTH1 MMP3 SOD1 BRCA2 FTH1 MMP9 SOD2 BTK G6PC MMP9 SOX9 C3 G6PD MT3 SPATA19 C4A GAD1 MTHFR SPI1 C4BPA GADD45B MUC2 SPP1 C69 GATA3 MX1 ST6GAL1 CALCB GBP1 MYB ST8SIA1 CASP4 GCLC MYC STAT5A CAV1 GCLC MYLK SUPV3L1 CCL1 GCLC MYOZ1 TACR1 CCL15 GCLC NCAM TAP1 CCL17 GCLM NFKB1 TAPBP CCL19 GCLM NFKB2 TCRB CCL2 GCNT1 NFKBIA TERT CCL20 GJB1 NFKBIE TF CCL20 GNAI2 NFKBIZ TFEC CCL22 GNB2L1 NGFB TFF3 CCL23 GNRH2 NK4 TFPI2 CCL28 GRIN1 NLRP2 TGM1 CCL3 GRIN2A NOD2 TGM2 CCL4 GRM2 NOS1 THBS1 CCL4 GRO-beta NOS2A THBS2 CCL5 GRO-gamma NOS2A TICAM1 CCL5 GSTP1 NOX1 TIFA CCND1 GUCY1A2 NPY1R TLR2 CCND2 GZMB NQO1 TLR9 CCND3 HAMP NR3C1 TNC CCR5 HAS1 NR4A2 TNF CCR7 HBE1 NRG1 TNFAIP2 CD209 HBZ NUAK2 TNFAIP3 DB1/ 147901903.2 297 NFkB gene list CD274 HGF OLR1 TNFRSF1B CD38 HIF1A OPN1SW TNFRSF4 CD3G HLA-B OPRD1 TNFRSF9 CD3G HLA-G OPRM1 TNFSF10 CD40 HMGN1 ORM1 TNFSF13B CD40LG HMOX1 Osterix TNFSF13B CD44 HOXA9 OXTR TNFSF15 CD48 HPSE PAFAH2 TNIP1 CD54 HSD11B2 PAX8 TNIP3 CD80 HSD17B8 PDE7A TP53 CD83 HSP90AA1 PDGFB TRAF1 CD86 ICOS PDYN TRAF2 CDK6 ICOS PENK TREM1 CDKN1A IDO1 PGK1 TRPC1 CDX1 IER2 PGLYRP1 TWIST1 CEBPD IER3 PGR UBE2M CFB IER3 PI3KAP1 UCP2 CFB IER3 PIGF UGCGL1 CFLAR IFI44L pIgR UPK1B CGM3 IFNB1 PIK3CA UPP1 CHI3L1 IFNG PIM1 VCAM1 CIDEA IGFBP1 PLA2 VEGFC CLDN2 IGFBP2 PLAU VIM COL1A2 IGFBP2 PLCD1 VPS53 CR2 IGHE PLK3 WNT10B CR2 IGHG1 POMC WT1 CREB3 IGHG2 PPARGC1B XDH CRP IGHG4 PPP5C XIAP CSF1 IGKC PRF1 YY1 CSF2 Iigp1 PRKACA ZNF366 CSF3 IL10 PRKCD CTSB IL11 PRL Table 5. List of IRAK1/4 dependency genes from FIG.4C (long IRAK1/4 gene signature) IRAK1/4 dependency genes PLS3 S1PR5 C10orf76 PCDHB13 HSBP1L1 WDFY4 C10orf91 PCDHB14 CDC42BPA GRK5 C15orf38 PCED1B PPP2R3A SREBF1 C2CD4C PCED1B-AS1 GNG12 STXBP5L C2CD5 PCSK5 PENK VARS2 C3orf18 PDLIM1 STC2 GAB2 CALHM2 PEAR1 DNAJC22 ZFP36L1 CAMK1D PFKP DB1/ 147901903.2 298 IRAK1/4 dependency genes SH3D19 CPNE7 CAPRIN2 PGAM1 GABRD HSPA2 CDH2 PGAM4 RAVER2 NAT8L CDHR1 PI15 ARHGEF26 DOK4 CEL PITX1 APBB2 IGF1R CEP72 PLEKHA8P1 BAI2 KHK CES3 PLEKHO1 DPEP1 KIRREL2 CES4A PPFIBP1 LGI2 COMTD1 CHST3 PPP2R2D PIP5K1A ZNF488 CLIC5 PPP3CB SOX18 CASC10 CMAS PRTFDC1 BMP4 QRICH2 CNNM2 PSTPIP2 TMC4 RBM17 CNTN1 PTENP1 KCNIP3 LSS COL27A1 PVRL3 CCNO PAX8 COL4A5 PWWP2B ULK4P2 PKN3 CPS1 PXDC1 FAM57A HELLS CRABP1 RNF208 SCARA3 FN3K CTBP2 ROBO1 CERS1 CDC42EP1 CUEDC2 RP11-184I16.4 BEND5 NFIX CXorf57 RP11-53O19.1 HAPLN3 BMS1 DAPK2 RP11-96H19.1 DNMBP STOX1 DDAH2 RPAP3 KIAA1522 SEMA4B DDX11 RTN1 PIR SUPV3L1 DDX11-AS1 SAMD11 GTF3C5 FAM198A DENND5B SAMD8 ECHDC3 RCOR2 DHTKD1 SCAF11 ICAM1 PDCD4 DNM1L SCD5 RAB3A PPAP2A DPCD SDHAP3 SDHA DDX12P DPY19L2 SEC14L2 C9orf116 ACY3 DUSP5P1 SEC31B MKI67 TSPAN10 EBF3 SEC61A2 LMTK3 NUP155 EFEMP2 SECTM1 MCM10 RIBC2 EGFR SFMBT2 ADM2 PLCXD1 ELK1 SFXN2 HSD17B14 TP53INP2 EPHB4 SHANK3 LOC102724002 GOLPH3 FAM155B SHISA3 KCNH2 WDR70 FAM175B SHISA7 PRAME BTRC FAM21C SIDT1 KIAA1279 SVIL FAM45A SKIDA1 LOC101929974 DTX4 FAM53B SLA2 ARHGAP21 DUSP5 FAM84B SLC12A7 SULT2B1 ECE1 FCER2 SLC16A6 ADCY6 MRPL43 FGD4 SLC16A9 GBF1 SKP2 FOXL2 SLC4A11 DB1/ 147901903.2 299 IRAK1/4 dependency genes TUBGCP2 SNHG3 FZD8 SLITRK5 CD19 MYRF GAS1 SMAD1 SPIRE2 ZFYVE27 GPC6 SNHG12 SH3PXD2B H2AFY2 GRIA3 SNORA61 AADAT NOLC1 GUCY1B3 SNORD104 FOXC1 SLC25A28 GYPE SOX1 ZBED3 WNK2 HDHD3 SPEF2 TSKU NDUFS6 HES4 SRRM3 NRARP SLC30A3 HIF1AN SUFU AMIGO2 LOC642846 HMGCS1 TARS PCBD1 NEURL1B HMX2 TCF7 TCAM1P ARMC4 HMX3 TEX15 FAM57B SFXN3 HOXB13 TGFBR3L LOC101929021 VASH2 HOXB6 THBD PCK2 NOTUM HSD17B8 TIAL1 CCDC127 VCL HSH2D TLX3 MGMT LOC100506901 IDE TM7SF3 C6orf147 CSTF2T INPP5A TMEM180 TGFB1I1 PRICKLE1 INPP5F TMEM191C DPP4 ZNF132 INPP5J TMEM255A ALX4 GPR153 IPO8 TMEM63C TACC2 ZMYND11 IRAK4 TRIM72 WLS DGCR5 ITPR2 TUBB3 PACSIN3 OXER1 ITPR3 TYSND1 NAPA-AS1 VTI1A JMJD1C UGT3A2 LINC00999 PCDHGC3 KAZALD1 ULK2 BAIAP3 MORC4 KCNQ5 UNC13D ANKH EIF3A KCNS3 USP54 VDAC2 PDCD11 KIAA1324 VENTX TAF3 SLC38A1 KIF11 VIM ECHS1 MC1R KLHL42 XPNPEP1 EFNA3 CBS KLLN YARS2 CORO6 AC002454.1 KRAS YPEL3 TCTN2 PDCD6 KREMEN2 ZDHHC16 HPS1 B4GALNT1 LAT ZDHHC6 DNAJB12 RPP38 LDB1 ZNF43 SPIB SUGT1P1 LGALS3BP ZNF438 SLC29A3 NEDD4L LINC00477 ZNF503 PHGDH PROCA1 LIPE ZNF503-AS2 PTMS SH3PXD2A LOC100288152 ZNF511 TMEM91 JAG2 LOC100506688 ZNF574 SEC24C FGFR3 LOC100506691 ZNF622 HGD TMEM191B LOC100507487 ZNF726 DB1/ 147901903.2 300 IRAK1/4 dependency genes MSS51 SEPHS1 LOC101927104 ZNF99 TEAD3 LOC100505761 LOC101927799 ZWINT LARP4B C21orf58 LOC101928913 ADM ZCCHC24 FADS1 LOC102723337 ALDOC ARHGEF16 TET1 LOC102724472 BNIP3 FOXO6 GBGT1 LPCAT1 CA3 FBXO18 KAT6B LRMP CD209 PPRC1 KIFC2 LRRC10B CSMD3 CCDC78 TAF5 LRRC20 DDIT4 RHBDL1 CASP7 LRRC27 FCGR2B SPINT1 PELI3 LTK FCGR2C STON2 PP7080 LY6G5C FIGN NUDT8 ATN1 LZTS2 GLIS2 NEBL KIAA1598 MAP2K6 SHISA8 EPAS1 FAM115A MASTL SOX5 FAM178A NKX3-2 MCIDAS TBC1D30 PI4K2A CHCHD10 MCMBP TLE6 SNED1 GPSM1 MDGA2 TLX1 STAM LRP4 METTL12 VAT1L PLOD2 CDT1 METTL20 VEGFA TM7SF2 EIF4EBP2 MMS19 ANXA4 FGD1 AASS MPPED2 APLN PCDHB6 ABCC6P1 MRPS16 C1QL4 CCNB3 ABCD2 MRPS35 CCDC102A MCMDC2 ADAMTS14 MSX1 CHDH EDRF1 AGAP4 MX1 EGLN3 NRM AGAP9 NDUFB8 ENO2 PPIF AIFM2 NEURL1 FADS2 ATF5 AKR1C1 NEUROG3 HK2 BRD9 AKR1E2 NFKB2 HSPA7 B3GALT4 ANK3 NIM1K IL17RB NET1 ANKRD33B NKD2 KLF2 TMEM169 ANO6 NLGN2 LAMC3 RPH3AL APBB1IP NNT LINC00263 DROSHA ARHGAP19 NNT-AS1 LOC101928092 RBMS2 ARNTL2 NT5DC2 LOC102724908 POLR3A ARSG NUDT13 MIR210HG TRIP13 ARTN OGDHL NRTN LPHN1 ASCC1 OVOL2 PFKFB4 ZMIZ1 ASUN OXCT1 SCD RP11-344B5.2 BAG3 P2RX7 SLC4A3 HNRNPF BEND4 P4HA1 SLC6A8 HSD17B7P2 BEX5 PABPC1L ZNF215 DB1/ 147901903.2 301 IRAK1/4 dependency genes SLIT1 BLNK PANK1 ZNF395 LOC648987 BTAF1 PAOX ACTR1A C10orf10 PAPD7 CCT5 C10orf12 PAPSS2 Table 6. List of IRAK1/4 dependency genes from FIG.10 (short IRAK1/4 gene signature) IRAK1/4 dependency genes KRAS COL27A1 DUSP5 COMTD1 SOX5 ARHGAP21 INPP5A ECHDC3 HMX2 PDLIM1 BRD9 PAOX TACC2 CAMK1D ZFYVE27 LPCAT1 AIFM2 SCAF11 LRMP ARSG ZNF438 DNAJB12 SLC38A1 PSTPIP2 FGD4 TUBGCP2 SLC12A7 VENTX GRK5 DNMBP ZMIZ1 AMIGO2 ANK3 JMJD1C ANO6 PCED1B ZNF622 ELK1 PRICKLE1 PCED1B−AS1 PWWP2B SFMBT2 CALHM2 BAG3 SFXN3 NRARP LINC00477 SLC29A3 DDIT4 NIM1K DB1/ 147901903.2 302 0 5 n O i e s W s t f a r - n o g A A A A A o + + / N / N / N / N / 2 p n N 1 0 s e e 5 R x-4 6 3 0 e 3 1 C s F n o A / A / A / A / A / A / Cp s e N N N N N N r 4 y / a 1 n s Koi t A s / A / A / A / A / A / a Ae R l N N N I e N N N d g n i mr e o s f Cn t o s e i t o s e i y F o n m p r n n m r n + + + + n Cs d i o o l d i o o l + + + + o e D f o D f o l r c c o c n i y n r , si i c b i u r o t n n e n o o i t t s s i i o , a b u ) ; &e s n o n n / e e b h n g d e e r r a d e y r a e o , n u a d e n o m n n i t a V e h t e h v t ï a ) d e n i t a h n i t a u n e d e r y x dI/ d a e n o d r n u p y s w x e r o D d n s n / e o p s e e r & r T ; a d z e d d e s s s x s e r T ; i m t o v t e o r r d n i p s o c o 4/ a e o p y b a e r r Ak ( e S d Rn n u i b s a e g r o r o A p v o ; n e o p s e r g g o o r v p o n 1 r n T e Hr a y D t y HT r A a t n y i c n i e v ï a e n r ( o r p e D 3 0 K C C D 3 A R I si s o t o n R / A e v ï e a v ï e a v ï e v ï e v ï e g a R N N a a a v i i N N N N ti D sn e s s c o l , , , , s i , 1 , , A, , 2 , , S 2 T r e e n 1 , L S A, T, 6 1 2 2 G e t l e p n L 1 , , e X L S 2 RA2 X 3 3 TA RT E 1 , L RA E t e a p 1 R , NI F HDA MF T X 3 F R H T, h / ll L XO 1 G K , PAT m t a n g s a o v t AK , A J 6 1 S F S T F A CM K , G, D1 2 S S , 2 Du f R A C 1 G T I- ( ) S C 1 g n A BX, , U2 A, H 6 1 R , S 1 , 3 d e e l y e c 2 / , V s HA T A , 2 D, 1 NT L D I P M K, 1 P S , , AA R DA 3 i , R C 2 T , ZMM P 1 C AT TMd n T O R ED NNPM vi Rn o Z r i EP , B E U T E I- 3 R , 1 , H N, Z T I N S, LP e W C 3 , K , T S OX2 C 2 - 3 G, 1 F ; N , p 3 B FA3 , 1 8 8 P , e t a 2 d t u T E C T LC BUA CTTG OA TK LD 1 X XY T L, XS CT FD, A N1 T F A NT F CX UN U X 5 3 8 F R T MZ KYEC - t n m G S C R 6 e 4 N D A D I MT P M S i t a p n oi r d t D ) 5 oi n a a c i L M f C S M ( r p s i ( ) S L L e s M R D D M M s A -S M L L A D M M M A ni a l l C M A A ll e - - - - 2 C . . t 7 n e ) G G G G 3 0 e l p L 9 ) 1 S 0 * 6 S ) 8 T C) e i 8 T C) 9 T C) T C* ) 9 1 l t b a m M5 4 D9 6 D2 3 ( ( 3 ( 0 ( 9 0 L2 2 L 4 L3 9 3 2 9 7 a P a S A6 ( M7 ( M3 ( M 2 M 3 M 3 L M 2 4 1 T A A A A / 1 B D 0 5 O W- A / A / A / A / A / 2 N N N N N 1 0 5-4 6 3 0 3 1 A / A A A N / A N / N / N / N A/ A / A / A A N N N / N / N ht + w - + + + + + o r g / + o N bu r o n e g u s n n i a o d Dp s e e n / e e p n e i r n o n o b o N N ar n a t n i y c i 4 C 0 3 A R e v e v N / R ï a ï N a N , 3 1 , , , , Y , F , 1 , , , 2 , X, , L, , N , , X, 3 , S 3 T T L RT W F 3 I F K, 2 - T , X; T A WRX2 1 K1 R B A 6 1 E T , 1 3 5 RA 2 T L A, S , , 1 5 P , ; , Y3 BUA TH C2 A J L XT C, MM P P , XP T TN F, R ANEX T 35 2 AS P R N C 1 E , A T T 6 X , C R , 4 : , 6 T L1 L, RATS , 1 S A , FD NAN, A , K6 K , RTN, 2 3 GORX A , 1 L A R K, , RU2 T 1 LDV T T I N, P , UT T S , R s RA1 Hs c 4 / 2 Z c i t n O GCit ] F 3 : s R n O CF , S A N 3 , ZNA A, 2 U3 X S B, 1 S 1 HA F R , E RG X C, E K 1 A R , E T D1 1 T, S 1 , , HR1 1 , T e C E g B, , 1 T e n 1 [ o i B C , T6 T R T ALD I K P N 1 AL XOe g 8 t a T o t t , RA3 A 6 C TF N1 P y T R RMME T , 2 M, 1 R, 3 , T, S P B 3 , 1 G OTMOD P B C WU N C o t + y u OL C MCAND D K TN E DL BOTI AT P F L BCMD N P T P T E B C T AC BL F KR S N A BN D K S )4 ) M ) ? ( 1 L ( M ( L M A L L L M M M M A A A A - - - 2 G 4 T G G 6 0 . 3 6 0 C* ( ) 8 T C* ) 2 T C* ) 6 L6 7 L5 9 1 0 L3 4 ( L0 7 ( L5 4 M3 M2 A7 7 7 9 7 M3 M 2 M 2 0 3 A0 4 1 A A A 1 3 1 / 1 B D 0 5 O W- A / A / A / A / 2 N N N N 1 0 5-4 6 3 0 3 1 A / A A A N / N / N / N A/ A / A A N N / N / N ht h h + w t t + o w r o w o g r r o g o g N N o N es r u o c e -1 n e e o n n N o o 3 N N + 7 5 0 3 R e / v e v e v R ï a ï ï N a N a N ,1 , , L N2 , R, , ET X, , L , , , S , X, 3 , , 2 , , , 1 N OA E 2 3 R BA TT P T 3 2 A , , , T C, THRN1 RAT L , S , T X R, , X3 T2 AA 6 HE, 1 3 5 N F, ANE T TF APMC T T PXP C BNL , 1 A , K F , S AX3 , 1 F AMD I NE N, TN5 A 3 , 1 P , K7 R E T, , UP T 1 DW K , P 2 A F 3 , 1 R B B ED C KO, , NAN T, RU2 XD RT CA , 3 RN5 LR D KUP T X S B, , TMA R A LP R , , 1 1 L CXT B X S , 1 BI , AS 5 L , KR R S P 1 , 3 , F R T X S LAT S G, T 1 E T A F T, R , 1 AMA , 6 1 1 A, 1 2 F, N 1 L RN6 , F 1 3 S GN P F S A, L F , , F , 1 RA2 G1 A R2 NL F A RD X , 1 OK, 2 K P 1 , , N P 1 B LRN B B DMN LOKV DP B CDT E A RD P T P LO BCPH BD I D PN LC U B B D CH, ZT S I AT P 3 F S A KT P A B C K A B E C R A E KR N L L L L M M M M A A A A 9 1 7 3 2 . 3 L1 9 L 7 8 0 3 L1 1 0 1 L6 9 9 1 M7 M0 M0 0 0 A7 7 0 A8 A0 M0 9 7 3 0 1 3 0 1 0 A0 4 2 0 2 1 / 1 B D 0 5 O W- A / A A A 2 N / N / N / N 1 0 5-4 6 3 0 3 1 A / A N / A N / A N / N A/ A / A A N N / N / N ht h w t o w r o g + + + r o g N o N , r 2 a + t 5 s o , t n a y o c i t z e b i , a a di d i n e o n N o n i t N a 2 + l o V m s I 7 n o 6 c 0 3 R e / v e R ï a v ï N a R / N R , , 1 , 2 , , , , 2 L , , , N, 2 , X, , L 3 , 2 , 2 , X, , L 3 LR AK, 2 A J S A ART B F E T CA 7 1 , H1 E TT E R B T T 1 , 1 P C LKE R B T L BWDM P P , T , T A, F, A J T T C A, F, ON CK, 3 RG, 1 T L E X B I, NA1 , 1 F A6 V, , S N , 1 F A6 V BDT K , D ,1 C L PX W R C F A, , F , S 1 N, 3 O C AAA , R T I R B F 3 3 5 LRT AE3 5 LRT GF L , F , 7 6 HU R5 S P X B P B 2 , E , RT P P X B, E , N3 T H K, D, T S A1 A H, , T S A1 A XA M WDC T, T , 1 KM, 3 2 K P, 1 1 , 1 L R2 A NS 6 , 1 L R2 S RX B K N L DNT S N LO AM L N A B OE F NT P X S C DL F A J A P B KN BOK A R T N P AC BD C GD K AC BD C )4 L M ( L L M L M M A M A A A 9 2 8 6 0 8 . 0 3 0 L1 M9 0 L 1 3 M3 L 8 3 5 L5 5 9 1 0 A0 0 0 A1 0 M A1 0 M1 A0 9 7 2 0 0 0 0 2 0 2 0 4 2 1 / 1 B D 0 5 O W- A / A N / A N / A N / A N / A / 2 N N1 0 5-4 6 3 0 3 1 A / A N / A N / A A A N / N / N / N A/ A A A A N / N / N / N / A N / N ht h w t h t h t o w r o w o w o g + + r r r - o g o g o g N N N o N ,4 x n i e r n u i a b t a s r o e a d n e n e n e e t i 1 x o o o n o n o y m c N N N N N , + 3 M + 7 A 7 H 0 3 R e / v e v e v A e v R ï a ï N a ï ï N a N N a N , , , 2 1 1 3 , , , , , , , , , , , , X, 3 S 2 X 3 , , 1 , A, , S 3 1 , , , 1 AT I KB 3 , 1 , , 2 A T, 5 P RAT L A RT E R, T L2 KS AX3 5 , 1 2 7 A, , 5 P , L B, A7 A 6 A RB 3 , 1 3 K AF LA N T2 F T TF F RNP LNWRS N 1 PW F F L T , J S 3 2 HAE T N, K , A, A J U T K AE T C M S , 3 M2 , , 5 R ONZ G, T , 2 A , K7 , 2 N1 T A , R6 , K , R, R ODX B K, RT , 2 L , X F B E X BDG D, 5 R ONK S N A RE P T T , CK E , 3 P , T 1 LDWAE T W1 L B, V TS T I , 2 T C C , F 2 N, P , T S A C F K, P 1 XP T C DA J H P , , 2 BD T , 1 CAT , 3 TLAE F R T X C, X T P , F , 3 X 1 EA R KN EE BL , H AD 1 AE T A, R, A, 2 , S N, B , L, 3 S AE LF 1 S 1 B FA G, 5 S L R, H , T T, , 1 B 3 I , HR F , 1 1 B, 2 A3 K AAU2 T , 1 B T AM, 7 G1 A , L R, , 1 HP T A , OA 2 , S A 6 P, 2 L C, T2 C TG1 L 1 LNT J R R A6 T X , E L C, L F NM S RNWDN A B DX P P T 1 LOA CP 1 B A T C T 1 LC BN KA NM1 G DMAX T S FM AANA TO ND P N B P ARK ODM, N3 T N , TN T X E S F , AA6 GD K B F P B A B E CAO B D G KP S R DA T G N A C N B G P C C D B L F I KT P RV BT E )4 y ht i st s ) ) S L M L , r o wa l ) B 5 M O M ( S t M Dc a i Bs E ( N ( A L M A a Mrf ms e A R L S A e R e n c ( M D Ax E A M 29 0 5 1 8 8 4 2 . 1 3 3 0 L5 L 2 8 L2 L3 L1 L 8 6 9 M8 1 M8 9 1 5 1 3 1 5 1 0 A0 0 1 0 A0 M0 M0 M0 M1 0 9 7 2 0 A 0 0 A0 A0 A0 4 2 0 2 0 2 0 2 0 2 1 / 1 B D 0 5 O W- A / A N / A N / A N / A / 2 N N 1 0 5-4 6 3 0 3 1 A / A A A A N / N / N / N / N A/ A A A N / A N / N / N / N ht h t h h w t t o w w w r o r o r o g o g + g r g N o N o N o N 2 e x n p s e n e n e o N e n a o o n o r N N N A 8 0 3 ev x T e e e ï a -t v ï a v ï a v ï N s o P N N a N , N, E 2 T T , X , , ) + , , , A1 , 2 , S , 2 , L, , , , 2 T , , X , S A, , S 2 T , , L, , NE P E R, FA3 DRX , , F AK , T, T AA , T NE , B C7 2 N HE E R , A3 R A, S , NE , BA3 S T , 1 AA T TI FN, 3 XA P J , R E T 1 L , WD T T, T AL T H, R AE T, 1 L C, T A P , X 6F 1 HX3 , 1 RM( GU PN5 P L B, N3 1 D , TD L P R , , 5 P R TR B N T , A , B E3 K , 1 C , T , T, 2 LT F I P , F 3 X F X S A B I F , P S , T 1 , B AS R5 P A R B, A I X3 1 CM , N2 K A , R T N T1 KN5 L1 D , TI , P 1 , X, 3 X FMR S AN K , AN RU AN5 A R D , T I F R , , U T X S LA F T I E2 1 LA 2 , K , R S T , 1 , A R, UP T X S LAA K , HRUP , 1 B, A KG1 A R , A R2 , 7 K T P T E L XRNAA F , 1 L 1 2 N H , A R , A R O2 G, AC F R , T L 1 2 , D1 RF 1 1 , 1 O CNW, 2 , 6 T S OK3 T6 GX B L RK3 6 1 2 , 1 CN7 6 TG1 1 B L RN3 T P, N P GN L BK DP B DXKF AC BDMMD A TM D PN ODLDD L BK DWMOD A K D N P N ODL S AT P P T P A C B F A J H P CN D K U R C B C F KA B R A CX B F K P T C P B C F R N )5 ) 4 ) 5 ) M ( M ( M 1 L M M ( ( L L A L L M M M M A A A A 39 4 8 7 0 2 . 0 6 3 0 L4 L0 L 6 7 L4 L 5 7 9 M8 1 M6 3 M5 0 1 M5 1 M5 1 1 0 A0 0 0 A0 A0 0 0 9 7 2 0 2 0 A 0 0 A0 4 2 0 2 0 2 1 / 1 B D 0 5 O W- A / A N / A / A / A / A / A / 2 N N N N N N 1 0 5-4 6 3 0 3 1 A / A A A A A N / N / N / N / N / A N / N A/ A / A / A A A A N N N / N / N / N / N ht h h w t t h t o w w w r h g e t r o r + + o r o r + + v w o g g g Oo r N o N o N o N G )2 1 e B n o A / n i e n e n e n e n N N m o o o o at N N N N i V ( 9 0 3 ev e a / / v e a v e a v e ï A R ï ï ï a v ï N N R N N N a N ,2 , , 2 , , 1 , S , 6 , , 1 , , , , , 1 , 1 , , , 1 , T L E B H Z, A TR FX, N3 5 , 1 , A F H2 T L R, S A, S 1 1 XL , RBAHX XR R L, A, S B 3 R O, , T , , X C, E I 2 R KGUP T LA R 2 H P , E T OA PNAN RP 3 T C3 CN , TTU3 TA C3 T A F S F 6 3 C AV TF , 6 , S D P R , , R 2 g ON, 2 L 1 1 T C BB E G, K T P 5 A , FMO R , 5 A , , 1 MR, 5 B , RT G, A3 5 AA RVA, 1 1 T n i CKH P MX W, C 7 , T , P T 1 L A RN N , 1 1 P T 1 L LN K , N EP T 1 L B, E , T P , S, T 1 L B, T 1 E , NS G, ANE d RP T, n BD e , C Z E, N, 3 R, AWI NE , 2 X B D , T I N, 2 X R O D , T I T, 2 X 1 A P 1 , F , S U 1 X R 5 O C2 X B K, TT S , 1 A 2 K , P T S C A 2 K P , T S L R2 N S LA 2 3 N T P 2 G LAA3 A R, P T B , N F, S P, E T A, LNA T P E T A, B , , N1 AE T A, OK B R 3 A F ONT , KL S , X NA S R T BM K , N K E XD 2 A S 1 R HR A LOK6 , 1 KHR 1 C MN L R D F L B D C S C F B D A E T S A TT R C C R Z HR B CD CDE BOD I G B KT P N DI K P T A E N A B KT P AC B C D P A )4 y h M r t i st s a ( , A S o t w l ) BB L L L L L / N Dc a a i s E M Mrf A M M M M A e m Re s n e c R A A A A Ax ( E 9 5 5 2 * 9 7 0 7 9 * 6 * 0 2 . 3 0 L7 M5 1 L3 M6 3 L 0 5 M0 L7 5 L4 7 L 7 2 7 9 8 L8 3 1 0 A0 0 0 A9 9 A3 7 M7 M7 M A7 A7 A7 7 M9 7 9 7 2 9 1 0 3 0 1 3 0 1 3 1 0 A 3 0 4 1 3 1 1 / 1 B D 0 5 O W- A / A N / A N / A N / A / 2 N N 1 0 5-4 6 3 0 3 1 A / A N / A N / A A N / N / N A/ A A A A N / N / N / N / N h h g d n e i t t e a + w t o w o b e p + + + r g r g + e r o N o N ni c i b u e r n o 3 o x o e n e n e n N + 7 D o o o +r N N N as o t y 0 c 1 3 ev e e e ï l a b a v ï v e ï v ï N t S a N a N a N , A6 , , N 2 , 1 , A , , , A , 2 , , , R , A 2 , X, , , , L , , , , A1 , 2 1 L , , 2 ME, 1 T E L R, 6 , N3 5 X R, A3 6 , NT E O, A3 6 , G NA R BA3 3 2 HT I R FX NT R, S T DTX T OAM K P DE P T L TM DE T CF ATM DE T T 3 A C, T T L D K , GUE T2 OA 2 A RE T 1 ,1 , N, S U2 1 F T C B2 , N K T P T, A , BM K T P , 2 B , RM K T P S , 5 , FM F I , K, 2 , 2 1 C, N, , F 3 X BN, 2 , 2 P 1 L AN, 2 S AD 6 P R, R CN N, X , , 1 2 GS R B, K, T 2 GN HA R , S R W , 1 DKS T E L1 D 2 , KS S R5 R, 1 D , HS F S T , X R D , HAMS 1 A Z RDI AU D I R 1 S 3 , 5 L CAA R T X S LAAA R S P T T LADA RR 2 S B, A ZRDANP T, 3 O C, K, T R 3 7 N, 1 , S N WA P 1 T P P X T S , J A , K, , L B7 , 2 F A R , O2 J CN, 1 K , A , 1 1 , 1 R O2 I N, 7 K , S, T 1 E A 1 2 E T , 1 L , H, K RT S 5 CF 7 S 5 RN6 S , 2 N, P , , 1 P B , AW,, P T X BR P B F K T 1 CWT I S R 1 L BKA E L X K S B D T T I N L KP XC BKWT I X LOKVTA NKS NB 3 TXR BXN E S B A B F A CA T G P S DX KN X A C B F U S CD R A B C E GA J A RE KTF P S R T B F T A P L L L L L M M M M M A A A A A *5 * 9 4 9 6 * 7 2 . 3 0 L 9 3 L 2 0 L9 L 5 0 8 9 M0 A0 3 3 8 M0 0 A0 M0 9 0 M0 L4 0 M9 1 0 0 0 9 7 3 0 A0 1 0 2 0 A0 A 2 0 2 0 0 4 2 1 / 1 B D 0 5 O W- A / A N / A / A / A / A / 2 N N N N N 1 0 5-4 6 3 0 3 1 A / A A A A A N / N / N / N / N / N A/ A / A / A / A / A N N N N N / N ht h t h h w o w t w t w r o g r + + o r o r + + o g N o g N o g N o N en e n e e e e o o n n n n N N o N o N o N o N 11 3 ev e e e e e ï a v ï a v ï v ï v ï v ï N N a N a N a N a N , , , , , , 2 , S , 2 , , 2 , X , , NE 3 R, , S , , 1 F , A T , , TN , H , 1 , R T , F AT A , A P BI T 5 K P P OA 2 A , , 3 , T C BNRN1 5 EXP , A 2 H, T 1 S S R 1 N, S , E 1 , LND I A, 7 I E , , A S L F A Z T I X3 N5 R GANE T, L R2 W 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Claims

CLAIMS 1. A method of treating an inflammatory disease or disorder, or a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), in a subject in need thereof, the method comprising administering to the subject Compound 8: or a salt, ester, solvate, optical of an isomer thereof.
Figure imgf000318_0001
2. The method of claim 1, wherein the inflammatory disease or disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis.
3. The method of claim 1, wherein: the AML is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML, or the MDS is MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, or MDS with a splicing factor mutation, optionally wherein the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1, SRSF2, SF3B1, or ZRSR2.
4. The method of claim 1 or 3, wherein: the subject has AML and the subject has a gene mutation in one or more of FLT3, TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, DB1/ 147901903.2 317 JAK2, ASXL1, ABL1, ATRX, BCORL1, KDM6A, PTPN11, TP53, CBL, CEBPA, FBXW7, HRAS, NRAS, IDH1, IDH2, NRAS, PDGFRA, SF3B1, ETV6, PHF6, GNAS, KRAS, NOTCH1, STAG2, SETBP1, GATA1, GATA2, WT1, SRSF2, GNAS, CEBPA, CALR, MPL, BCL11A, ATM, CTCF, U2AF1, TYK2, FBX, RUI, RAD21, or MLL3, or the subject has MDS and the subject has a gene mutation in one or more of U2AF1, FLT3, ASXL1, BCORL1, BRAF, CBL, CDKN2A, DNMT3A, FBXW7, GATA2, IDH2, KRAS, NOTCH1, NRAS, PDGFRA, PTEN, PTPN11, TET2, TP53, EZH2, HRAS, KIT, MPL, PHF6, RUNX1, WT1, ABL1, CEBPA, ETV6, IDH2, KDM6A, KIT, KRAS, PTEN, RUNX1, SF3B1, or ZRSR2. 5. The method of any one of claims 1 to 4, wherein Compound 8 has an IRAK1 IC50 of less than about 40 nM, optionally less than about 5 nM, and/or a FLT3 IC50 of less than about 2.
5 nM.
6. The method of any one of claims 1 to 5, wherein Compound 8 has an IRAK4:IRAK1 inhibitory potency ratio of less than about 40.
7. The method of any one of claims 1 to 6, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes and/or decreased expression of one or more IRAK1/4-associated genes.
8. The method of claim 7, wherein the subject in need thereof has elevated expression and/or decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject.
9. The method of claim 7 or 8, wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, DB1/ 147901903.2 318 HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, DB1/ 147901903.2 319 FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395, optionally wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, DB1/ 147901903.2 320 PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3.
10. The method of claim 7 or 8, wherein the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, DB1/ 147901903.2 321 KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, DB1/ 147901903.2 322 VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395, optionally wherein the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3.
11. The method of any one of claims 1 to 10, wherein upon administration to the subject, Compound 8 decreases the expression of one or more IRAK1/4-associated genes in the subject, and/or increases the expression of one or more IRAK1/4-associated genes in the subject.
12. The method of any one of claims 1 to 10, wherein upon administration to the subject, Compound 8 decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject, and/or increases the expression of one or more IRAK1/4-associated genes found to be decreased in the subject.
13. The method of claim 12, wherein the administration of Compound 8 decreases the expression of the one or more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of the one or more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8.
14. The method of any one of claims 11 to 13, wherein administration of Compound 8 decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more IRAK1/4-associated genes found to be decreased in the subject compared to a healthy control subject. DB1/ 147901903.2 323
15. The method of any one of claims 11 to 14, wherein upon administration to the subject, Compound 8 decreases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, DB1/ 147901903.2 324 AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, DB1/ 147901903.2 325 LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject, optionally wherein the compound decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject.
16. The method of any one of claims 11 to 14, wherein upon administration to the subject, Compound 8 increases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, DB1/ 147901903.2 326 NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, DB1/ 147901903.2 327 SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject, optionally wherein the compound increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject.
17. The method of any one of claims 1 to 16, wherein the subject in need thereof has elevated expression of one or more NFκB-associated genes, and/or decreased expression of one or more NFκB-associated genes.
18. The method of claim 17, wherein the subject in need thereof has elevated expression of one or more NFκB-associated genes compared to a healthy control subject, and/or decreased expression of one or more NFκB-associated genes compared to a healthy control subject.
19. The method of claim 17 or 18, wherein the subject in need thereof has elevated expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, DB1/ 147901903.2 328 ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, DB1/ 147901903.2 329 SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366.
20. The method of claim 17 or 18, wherein the subject in need thereof has decreased expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, DB1/ 147901903.2 330 KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366.
21. The method of any one of claims 1 to 20, wherein upon administration to the subject, Compound 8 decreases the expression of one or more NFκB-associated genes in the subject, and/or increases the expression of one or more NFκB-associated genes in the subject.
22. The method of any one of claims 1 to 20, wherein upon administration to the subject, Compound 8 decreases the expression of one or more NFκB-associated genes found to be elevated in the subject, and/or increases the expression of one or more NFκB-associated genes found to be decreased in the subject.
23. The method of claim 21 or 22, wherein the administration of Compound 8 decreases the expression of the one or more NFκB-associated genes found to be elevated in the subject DB1/ 147901903.2 331 before the administration of Compound 8, and/or increases the expression of the one or more NFκB-associated genes found to be decreased in the subject before the administration of Compound 8.
24. The method of any one of claims 21 to 23, wherein upon administration to the subject, Compound 8 decreases the expression of one or more NFκB-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more NFκB-associated genes found to be decreased in the subject compared to a healthy control subject.
25. The method of any one of claims 21 to 24, wherein upon administration to the subject, Compound 8 decreases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, DB1/ 147901903.2 332 Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject.
26. The method of any one of claims 21 to 24, wherein upon administration to the subject, Compound 8 increases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, DB1/ 147901903.2 333 CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, DB1/ 147901903.2 334 TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject.
27. The method of any one of claims 1 to 26, wherein the subject in need thereof has elevated secretion of one or more cytokines, optionally wherein the one or more cytokines are selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM- CSF, and IFN-γ.
28. The method of claim 27, wherein the subject in need thereof has elevated secretion of one or more cytokines compared to a healthy control subject, optionally wherein the one or more cytokines are selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ.
29. The method of claim 27 or 28, wherein Compound 8 decreases the secretion of one or more cytokines in the subject, optionally wherein the compound decreases the secretion of one or more cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL- 17, IL-23, GM-CSF, and IFN-γ in the subject.
30. The method of claim 27 or 28, wherein Compound 8 decreases the secretion of one or more cytokines found to be elevated in the subject, optionally wherein the compound decreases the secretion of one or more cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM-CSF, and IFN-γ in the subject.
31. The method of any one of claims 27 to 30, wherein the administration of Compound 8 decreases the expression of the one or more cytokines found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of the one or more cytokines found to be decreased in the subject before the administration of Compound 8. DB1/ 147901903.2 335
32. The method of any one of claims 27 to 31, wherein upon administration to the subject, Compound 8 decreases the expression of one or more cytokines found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more cytokines found to be decreased in the subject compared to a healthy control subject.
33. The method of any one of claims 1 to 32, wherein Compound 8 is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1.
34. The method of any one of claims 1 to 33, wherein Compound 8 provides sustained treatment of the inflammatory disease or disorder, or the cancer selected from AML and MDS in the subject, optionally wherein the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. 35. The method of any one of claims 1 to 34, wherein: the administration comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration; and/or Compound 8 is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight; and/or Compound 8 is administered to the subject in a dosage of from about 0.
35 mg to about 70,000 mg; and/or Compound 8 is administered to the subject daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once a week, twice a month, or once a month.
36. The method of any one of claims 1 to 32, wherein Compound 8 treats the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject during the time period that the compound is administered to the subject. DB1/ 147901903.2 336
37. The method of any one of claims 1 to 36, wherein Compound 8 continues to treat the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject after the administration is stopped, optionally wherein Compound 8 continues to treat the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped.
38. The method of any one of claims 1 to 37, further comprising administering to the subject one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF- 1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor; optionally comprising administering to the subject at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
39. The method of claim 38, wherein: the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof; and/or DB1/ 147901903.2 337 the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, or acalabrutinib or a pharmaceutically acceptable salt thereof; and/or the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof; and/or the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof; and/or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
40. The method of claim 38 or 39, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject; optionally wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof; optionally wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof.
41. A method of determining whether a subject with a disease or disorder selected from an inflammatory disease or disorder, and a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), can be treated by administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, the method comprising: determining whether the subject has an elevated expression of one or more IRAK1/4- associated genes and/or a decreased expression of one or more IRAK1/4-associated genes, DB1/ 147901903.2 338 wherein the IRAK1/4-associated genes are selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, DB1/ 147901903.2 339 C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11-184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395; optionally wherein the IRAK1/4-associated genes are selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, DB1/ 147901903.2 340 FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3.
42. The method of claim 41, wherein the subject has elevated expression of one or more IRAK1/4-associated genes compared to a healthy control subject and/or a decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject.
43. The method of claim 41 or 42, wherein the subject in need thereof has an elevated expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, DB1/ 147901903.2 341 GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, DB1/ 147901903.2 342 SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395; optionally wherein the subject in need thereof has elevated expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3.
44. The method of claim 41 or 42, wherein the subject in need thereof has a decreased expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, DB1/ 147901903.2 343 STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, DB1/ 147901903.2 344 METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395, optionally wherein the subject in need thereof has decreased expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3.
45. The method of any one of claims 41 to 44, wherein Compound 8 decreases the expression of one or more IRAK1/4-associated genes in the subject, and/or increases the expression of one or more IRAK1/4-associated genes in the subject. DB1/ 147901903.2 345
46. The method of any one of claims 41 to 44, wherein Compound 8 decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject, and/or increases the expression of one or more IRAK1/4-associated genes found to be decreased in the subject.
47. The method of claim 45 or 46, wherein the administration of Compound 8 decreases the expression of the one or more IRAK1/4-associated genes found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of the one or more IRAK1/4-associated genes found to be decreased in the subject before the administration of Compound 8.
48. The method of any one of claims 45 to 47, wherein Compound 8 decreases the expression of one or more IRAK1/4-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more IRAK1/4- associated genes found to be decreased in the subject compared to a healthy control subject.
49. The method of any one of claims 45 to 48, wherein Compound 8 decreases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, DB1/ 147901903.2 346 TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, DB1/ 147901903.2 347 NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject; optionally wherein the compound decreases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject.
50. The method of any one of claims 45 to 48, wherein Compound 8 increases the expression of one or more IRAK1/4-associated genes selected from: PLS3, HSBP1L1, CDC42BPA, PPP2R3A, GNG12, PENK, STC2, DNAJC22, SH3D19, GABRD, RAVER2, ARHGEF26, APBB2, BAI2, DPEP1, LGI2, PIP5K1A, SOX18, BMP4, TMC4, KCNIP3, CCNO, ULK4P2, FAM57A, SCARA3, CERS1, BEND5, HAPLN3, DNMBP, KIAA1522, PIR, GTF3C5 ECHDC3, ICAM1, RAB3A, SDHA, C9orf116, MKI67, LMTK3, MCM10, ADM2, HSD17B14, LOC102724002, KCNH2, PRAME, KIAA1279, LOC101929974, ARHGAP21, DB1/ 147901903.2 348 SULT2B1, ADCY6, GBF1, TUBGCP2, CD19, SPIRE2, SH3PXD2B, AADAT, FOXC1, ZBED3, TSKU, NRARP, AMIGO2, PCBD1, TCAM1P, FAM57B, LOC101929021, PCK2, CCDC127, MGMT, C6orf147, TGFB1I1, DPP4, ALX4, TACC2, WLS, PACSIN3, NAPA-AS1, LINC00999, BAIAP3, ANKH, VDAC2, TAF3, ECHS1, EFNA3, CORO6, TCTN2, HPS1, DNAJB12, SPIB, SLC29A3, PHGDH, PTMS, TMEM91, SEC24C, HGD, MSS51, TEAD3, LARP4B, ZCCHC24, ARHGEF16, FOXO6, FBXO18, PPRC1, CCDC78, RHBDL1, SPINT1, STON2, NUDT8, NEBL, EPAS1, FAM178A, PI4K2A, SNED1, STAM, PLOD2, TM7SF2, FGD1, PCDHB6, CCNB3, MCMDC2, EDRF1, NRM, PPIF, ATF5, BRD9, B3GALT4, NET1, TMEM169, RPH3AL, DROSHA, RBMS2, POLR3A, TRIP13, LPHN1, ZMIZ1, RP11-344B5.2, HNRNPF, HSD17B7P2, SLIT1, LOC648987, ACTR1A, CCT5, S1PR5, WDFY4, GRK5, SREBF1, STXBP5L, VARS2, GAB2, ZFP36L1, CPNE7, HSPA2, NAT8L, DOK4, IGF1R, KHK, KIRREL2, COMTD1, ZNF488, CASC10, QRICH2, RBM17, LSS, PAX8, PKN3, HELLS, FN3K, CDC42EP1, NFIX, BMS1, STOX1, SEMA4B, SUPV3L1, FAM198A, RCOR2, PDCD4, PPAP2A, DDX12P, ACY3, TSPAN10, NUP155, RIBC2, PLCXD1, TP53INP2, GOLPH3, WDR70, BTRC, SVIL, DTX4, DUSP5, ECE1, MRPL43, SKP2, SNHG3, MYRF, ZFYVE27, H2AFY2, NOLC1, SLC25A28, WNK2, NDUFS6, SLC30A3, LOC642846, NEURL1B, ARMC4, SFXN3, VASH2, NOTUM, VCL, LOC100506901, CSTF2T, PRICKLE1, ZNF132, GPR153, ZMYND11, DGCR5, OXER1, VTI1A, PCDHGC3, MORC4, EIF3A, PDCD11, SLC38A1, MC1R, CBS, AC002454.1, PDCD6, B4GALNT1, RPP38, SUGT1P1, NEDD4L, PROCA1, SH3PXD2A, JAG2, FGFR3, TMEM191B, SEPHS1, LOC100505761, C21orf58, FADS1, TET1, GBGT1, KAT6B, KIFC2, TAF5, CASP7, PELI3, PP7080, ATN1, KIAA1598, FAM115A, NKX3-2, CHCHD10, GPSM1, LRP4, CDT1, EIF4EBP2, AASS, ABCC6P1, ABCD2, ADAMTS14, AGAP4, AGAP9, AIFM2, AKR1C1, AKR1E2, ANK3, ANKRD33B, ANO6, APBB1IP, ARHGAP19, ARNTL2, ARSG, ARTN, ASCC1, ASUN, BAG3, BEND4, BEX5, BLNK, BTAF1, C10orf10, C10orf12, C10orf76, C10orf91, C15orf38, C2CD4C, C2CD5, C3orf18, CALHM2, CAMK1D, CAPRIN2, CDH2, CDHR1, CEL, CEP72, CES3, CES4A, CHST3, CLIC5, CMAS, CNNM2, CNTN1, COL27A1, COL4A5, CPS1, CRABP1, CTBP2, CUEDC2, CXorf57, DAPK2, DDAH2, DDX11, DDX11-AS1, DENND5B, DHTKD1, DNM1L, DPCD, DPY19L2, DUSP5P1, EBF3, EFEMP2, EGFR, ELK1, EPHB4, FAM155B, FAM175B, FAM21C, FAM45A, FAM53B, FAM84B, FCER2, FGD4, FOXL2, FZD8, GAS1, GPC6, GRIA3, GUCY1B3, GYPE, HDHD3, HES4, HIF1AN, HMGCS1, HMX2, DB1/ 147901903.2 349 HMX3, HOXB13, HOXB6, HSD17B8, HSH2D, IDE, INPP5A, INPP5F, INPP5J, IPO8, IRAK4, ITPR2, ITPR3, JMJD1C, KAZALD1, KCNQ5, KCNS3, KIAA1324, KIF11, KLHL42, KLLN, KRAS, KREMEN2, LAT, LDB1, LGALS3BP, LINC00477, LIPE, LOC100288152, LOC100506688, LOC100506691, LOC100507487, LOC101927104, LOC101927799, LOC101928913, LOC102723337, LOC102724472, LPCAT1, LRMP, LRRC10B, LRRC20, LRRC27, LTK, LY6G5C, LZTS2, MAP2K6, MASTL, MCIDAS, MCMBP, MDGA2, METTL12, METTL20, MMS19, MPPED2, MRPS16, MRPS35, MSX1, MX1, NDUFB8, NEURL1, NEUROG3, NFKB2, NIM1K, NKD2, NLGN2, NNT, NNT-AS1, NT5DC2, NUDT13, OGDHL, OVOL2, OXCT1, P2RX7, P4HA1, PABPC1L, PANK1, PAOX, PAPD7, PAPSS2, PCDHB13, PCDHB14, PCED1B, PCED1B-AS1, PCSK5, PDLIM1, PEAR1, PFKP, PGAM1, PGAM4, PI15, PITX1, PLEKHA8P1, PLEKHO1, PPFIBP1, PPP2R2D, PPP3CB, PRTFDC1, PSTPIP2, PTENP1, PVRL3, PWWP2B, PXDC1, RNF208, ROBO1, RP11- 184I16.4, RP11-53O19.1, RP11-96H19.1, RPAP3, RTN1, SAMD11, SAMD8, SCAF11, SCD5, SDHAP3, SEC14L2, SEC31B, SEC61A2, SECTM1, SFMBT2, SFXN2, SHANK3, SHISA3, SHISA7, SIDT1, SKIDA1, SLA2, SLC12A7, SLC16A6, SLC16A9, SLC4A11, SLITRK5, SMAD1, SNHG12, SNORA61, SNORD104, SOX1, SPEF2, SRRM3, SUFU, TARS, TCF7, TEX15, TGFBR3L, THBD, TIAL1, TLX3, TM7SF3, TMEM180, TMEM191C, TMEM255A, TMEM63C, TRIM72, TUBB3, TYSND1, UGT3A2, ULK2, UNC13D, USP54, VENTX, VIM, XPNPEP1, YARS2, YPEL3, ZDHHC16, ZDHHC6, ZNF43, ZNF438, ZNF503, ZNF503-AS2, ZNF511, ZNF574, ZNF622, ZNF726, ZNF99, ZWINT, ADM, ALDOC, BNIP3, CA3, CD209, CSMD3, DDIT4, FCGR2B, FCGR2C, FIGN, GLIS2, SHISA8, SOX5, TBC1D30, TLE6, TLX1, VAT1L, VEGFA, ANXA4, APLN, C1QL4, CCDC102A, CHDH, EGLN3, ENO2, FADS2, HK2, HSPA7, IL17RB, KLF2, LAMC, LINC00263, LOC101928092, LOC102724908, MIR210HG, NRTN, PFKFB4, SCD, SLC4A3, SLC6A8, ZNF215, and ZNF395 in the subject; optionally wherein the compound increases the expression of one or more IRAK1/4-associated genes selected from: KRAS, SOX5, HMX2, TACC2, AIFM2, ZNF438, FGD4, GRK5, ANK3, ZNF622, PWWP2B, SFXN3, SLC29A3, COL27A1, ARHGAP21, PDLIM1, CAMK1D, SCAF11, DNAJB12, TUBGCP2, DNMBP, JMJD1C, ELK1, SFMBT2, NRARP, DDIT4, DUSP5, INPP5A, BRD9, ZFYVE27, LRMP, SLC38A1, SLC12A7, ZMIZ1, ANO6, PRICKLE1, CALHM2, LINC00477, NIM1K, COMTD, ECHDC3, PAOX, LPCAT1, ARSG, PSTPIP2, VENTX, AMIGO2, PCED1B, PCED1B−AS1, and BAG3 in the subject. DB1/ 147901903.2 350
51. A method of determining whether a subject with a disease or disorder selected from an inflammatory disease or disorder, and a cancer selected from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), can be treated by the administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, the method comprising: determining whether the subject has an elevated expression of one or more NFκB- associated genes, and/or a decreased expression of one or more NFκB-associated genes, wherein the NFκB-associated genes are selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, DB1/ 147901903.2 351 LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366.
52. The method of claim 51, wherein the subject has elevated expression of one or more NFκB-associated genes compared to a healthy control subject and/or a decreased expression of one or more IRAK1/4-associated genes compared to a healthy control subject.
53. The method of claim 51 or 52, wherein the subject in need thereof has an elevated expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, DB1/ 147901903.2 352 CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, DB1/ 147901903.2 353 TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366.
54. The method of claim 51 or 52, wherein the subject in need thereof has a decreased expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, DB1/ 147901903.2 354 NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366.
55. The method of any one of claims 51 to 54, wherein Compound 8 decreases the expression of one or more NFκB-associated genes in the subject, and/or increases the expression of one or more NFκB-associated genes in the subject.
56. The method of any one of claims 51 to 54, wherein Compound 8 decreases the expression of one or more NFκB-associated genes found to be elevated in the subject, and/or increases the expression of one or more NFκB-associated genes found to be decreased in the subject.
57. The method of claim 55 or 56, wherein Compound 8 decreases the expression of one or more NFκB-associated genes found to be elevated in the subject before the administration of Compound 8, and/or increases the expression of one or more NFκB-associated genes found to be decreased in the subject before the administration of Compound 8. DB1/ 147901903.2 355
58. The method of any one of claims 55 to 57, wherein Compound 8 decreases the expression of one or more NFκB-associated genes found to be elevated in the subject compared to a healthy control subject, and/or increases the expression of one or more NFκB-associated genes found to be decreased in the subject compared to a healthy control subject.
59. The method of any one of claims 55 to 58, wherein Compound 8 decreases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, DB1/ 147901903.2 356 NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject.
60. The method of any one of claims 55 to 58, wherein Compound 8 increases the expression of one or more NFκB-associated genes selected from: A4, ABCA1, ABCB1, ABCB4, ABCB9, ABCC6, ABCG5, ABCG8, ADAM19, ADH1A, ADORA1, ADORA2A, ADRA2B. AFP, AGER, AGT, AHCTF1, AICDA, AKR1C1, ALOX12, ALOX5, AMACR, AMH, ANGPT1, APOBEC2, APOC3, APOD, APOE, AQP4, AR, ARFRP1, ART1, ASPH, ASS1, ATP1A2, B2M, BACE1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BCL3, BDKRB1, BDKRB1, BDNF, BGN, BLIMP1 /PRDM1, BLNK, BLR1, BMI1, BMP2, BMP4, BNIP3, BRCA2, BTK, C3, C4A, C4BPA, C69, CALCB, CASP4, CAV1, CCL1, CCL15, CCL17, CCL19, CCL2, CCL20, CCL22, CCL23, CCL28, CCL3, CCL4, CCL5, CCND1, CCND2, CCND3, CCR5, CCR7, CD209, CD274, CD38, CD3G, CD40, CD40LG, CD44, CD48, CD54, CD80, CD83, CD86, CDK6, CDKN1A, CDX1, CEBPD, CFB, CFLAR, CGM3, CHI3L1, CIDEA, CLDN2, COL1A2, CR2, CREB3, CRP, CSF1, CSF2, CSF3, CTSB, CTSL1, CXCL1, CXCL10, CXCL11, CXCL3, CXCL5, CXCL6, CXCL9, CYP19A1, CYP27B1, CYP2C11, CYP2E1, CYP7B1, DCTN4, DEFB2, DIO2, DMP1, DNASE1L2, DPYD, DUSP1, E2F3, EBI3, DB1/ 147901903.2 357 EDN1, EGFR, EGR1, ELF3, ENG, ENO2, EPHA1, EPO, ERBB2, ERVWE1, F11R, F3, F8, FABP6, FAM148A, FAS, FASLG, FCER2. FCER2/CD23, FCGRT, FGF8, FN1, FOS, FSTL3, FTH1, G6PC, G6PD, GAD1, GADD45B, GATA3, GBP1, GCLC, GCLM, GCNT1, GJB1, GNAI2, GNB2L1, GNRH2, GRIN1, GRIN2A, GRM2, GRO-beta, GRO-gamma, GSTP1, GUCY1A2, GZMB, HAMP, HAS1, HBE1, HBZ, HGF, HIF1A, HLA-B, HLA-G, HMGN1, HMOX1, HOXA9, HPSE, HSD11B2, HSD17B8, HSP90AA1, ICOS, IDO1, IER2, IER3, IFI44L, IFNB, IFNG, IGFBP1, IGFBP2, IGHE, IGHG1, IGHG2, IGHG4, IGKC, Iigp1, IL10, IL11, IL12A, IL12B, IL13, IL15, IL17, IL1A, IL1B, IL1RN, IL2, IL23A, IL27, IL2RA, IL6, IL8, IL8RA, IL8RB, IL9, INHBA, IRF1, IRF2, IRF4, IRF7, JMJD3, JUNB, KC, KCNK5, KCNN2, KISS1, KITLG, KLF10, KLK3, KLRA1, KRT15, KRT3, KRT5, KRT6B, LAMB2, LBP, LCN2, LEF1, LGALS3, LIPG, LTA, LTB, LTF, LYZ, MADCAM1, MAP4K1, MBP, MDK, MMP1, MMP3, MMP9, MT3, MTHFR, MUC2, MX1, MYB, MYC, MYLK, MYOZ1, NCAM, NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIZ, NGFB, NK4, NLRP2, NOD2, NOS1, NOS2A, NOX1, NPY1R, NQO1, NR3C1, NR4A2, NRG1, NUAK2, OLR1, OPN1SW, OPRD1, OPRM1, ORM1, Osterix, OXTR, PAFAH2, PAX8, PDE7A, PDGFB, PDYN, PENK, PGK1, PGLYRP1, PGR, PI3KAP1, PIGF, pIgR, PIK3CA, PIM1, PLA2, PLAU, PLCD1, PLK3, POMC, PPARGC1B, PPP5C, PRF1, PRKACA, PRKCD, PRL, PSMB9, PSME1, PSME2, PTAFR,, PTEN, PTGDS, PTGES, PTGIS, PTGS2, PTHLH, PTPN1, PTPN13, PTS, PTX3, PYCARD, RAG1, RAG2, RBBP4, Rdh1, Rdh7, REL, RELB, REV3L, RIPK2, S100A10, S100A4, S100A6, SAA1, SAA2, SAA, SAT1, SCNN1A, SDC4, SELE, SELP, SELS, SENP2, SERPINA1, SERPINA2, SERPINA3, SERPINB1, SERPINE1, PAI-1, SERPINE2, SH3BGRL, SKALP, PI3, SKP2, SLC11A2, SLC16A1, SLC3A2, SLC6A6, Slfn2, SNAI1, SOD1, SOD2, SOX9, SPATA19, SPI1, SPP1, ST6GAL1, ST8SIA1, STAT5A, SUPV3L1, TACR1, TAP1, TAPBP, TCRB, TERT, TF, TFEC, TFF3, TFPI2, TGM1, TGM2, THBS1, THBS2, TICAM1, TIFA, TLR2, TLR9, TNC, TN, TNFAIP2, TNFAIP3, TNFRSF1B, TNFRSF4, TNFRSF9, TNFSF10, TNFSF13B, TNFSF13B, TNFSF15, TNIP1, TNIP3, TP53, TRAF1, TRAF2, TREM1, TRPC1, TWIST1, UBE2M, UCP2, UGCGL1, UPK1B, UPP1, VCAM1, VEGFC, VIM, VPS53, WNT10B, WT1, XDH, XIAP, YY1, and ZNF366 in the subject.
61. A method of determining whether a subject with a disease or disorder selected from an inflammatory disease or disorder, or a cancer selected from acute myeloid leukemia (AML) DB1/ 147901903.2 358 and myelodysplastic syndrome (MDS), can be treated by the administration of Compound 8 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, the method comprising: determining whether the subject has an elevated secretion of one or more cytokines selected from: TNF-α, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-23, GM- CSF, and IFN-γ.
62. The method of claim 61, wherein the subject has elevated expression of one or more cytokines compared to a healthy control subject and/or a decreased expression of one or more cytokines compared to a healthy control subject.
63. The method of any one of claims 41 to 62, further comprising administering to the subject Compound 8: or a salt, ester, solvate, optical
Figure imgf000360_0001
of an isomer thereof.
64. The method of any one of claims 41 to 63, wherein the inflammatory disease or disorder is selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, atopic dermatitis, and colitis.
65. The method of any one of claims 41 to 63, wherein: the AML is relapsed AML, refractory AML, relapsed/refractory AML, AML with resistance to hypomethylating agents, AML with resistance to venetoclax, AML with resistance to hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML, optionally DB1/ 147901903.2 359 wherein the subject has AML and the subject has a gene mutation in one or more of FLT3, TET2, KIT, BCOR, BRAF, CDKN2A, UTX, ZRSR2, NPM1, PTEN, DNMT3A, EZH2, RUNX1, JAK2, ASXL1, ABL1, ATRX, BCORL1, KDM6A, PTPN11, TP53, CBL, CEBPA, FBXW7, HRAS, NRAS, IDH1, IDH2, NRAS, PDGFRA, SF3B1, ETV6, PHF6, GNAS, KRAS, NOTCH1, STAG2, SETBP1, GATA1, GATA2, WT1, SRSF2, GNAS, CEBPA, CALR, MPL, BCL11A, ATM, CTCF, U2AF1, TYK2, FBX, RUI, RAD21, or MLL3; and/or the MDS is MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2, optionally wherein the subject has MDS and has a gene mutation in U2AF1, FLT3, ASXL1, BCORL1, BRAF, CBL, CDKN2A, DNMT3A, FBXW7, GATA2, IDH2, KRAS, NOTCH1, NRAS, PDGFRA, PTEN, PTPN11, TET2, TP53, EZH2, HRAS, KIT, MPL, PHF6, RUNX1, WT1, ABL1, CEBPA, ETV6, IDH2, KDM6A, KIT, KRAS, PTEN, RUNX1, SF3B1, or ZRSR2; and/or optionally wherein the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1, SRSF2, SF3B1, or ZRSR2.
66. The method of any one of claims 41 to 65, wherein Compound 8 has an IRAK1 IC50 of less than about 40 nM, optionally an IRAK4 IC50 of less than about 5 nM, and/or an FLT3 IC50 of less than about 2.5 nM.
67. The method of any one of claims 41 to 66, wherein Compound 8 has IRAK4:IRAK1 inhibitory potency ratio of less than about 40.
68. The method of any one of claims 41 to 67, wherein Compound 8 is more effective at inhibiting cancer cell colony formation and/or cancer progenitor cell function when compared to a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1.
69. The method of any one of claims 41 to 68, wherein Compound 8 provides sustained treatment of the inflammatory disease/disorder, AML, or MDS in the subject, optionally wherein the sustained treatment is greater than the treatment provided from a compound which inhibits IRAK1 without inhibiting IRAK4 or inhibits IRAK4 without inhibiting IRAK1. DB1/ 147901903.2 360
70. The method of any one of claims 41 to 69, wherein: the administration comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration; and/or Compound 8 is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg/kg subject body weight; and/or Compound 8 is administered to the subject in a dosage of from about 0.35 mg to about 70,000 mg; and/or Compound 8 is administered to the subject daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once a week, twice a month, or once a month.
71. The method of any one of claims 41 to 70, wherein Compound 8 treats the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject during the time period that the compound is administered to the subject.
72. The method of any one of claims 41 to 71, wherein Compound 8 continues to treat the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject after the administration is stopped, optionally wherein Compound 8 continues to treat the inflammatory disease or disorder, or the cancer selected from AML and MDS, in the subject for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, or about a month after the administration is stopped.
73. The method of any one of claims 41 to 72, further comprising administering to the subject one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, DB1/ 147901903.2 361 a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF- 1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor; optionally comprising administering to the subject at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
74. The method of claim 73, wherein: the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof; and/or the BTK inhibitor is ibrutinib or acalabrutinib or a pharmaceutically acceptable salt of any one thereof; and/or the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof; and/or the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof; and/or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
75. The method of claim 73 or 74, wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject; optionally wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject compared to a subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a DB1/ 147901903.2 362 pharmaceutically acceptable salt thereof; optionally wherein the combination of Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, increases survival of the subject by about 10% to 200%, about 10% to 175%, about 20% to 175%, or about 20% to 150% compared to the subject administered either Compound 8, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or venetoclax, or a pharmaceutically acceptable salt thereof. DB1/ 147901903.2 363
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