[go: up one dir, main page]

WO2021078937A1 - Traitement de maladies liées à la stat3 par des chélateurs de fer - Google Patents

Traitement de maladies liées à la stat3 par des chélateurs de fer Download PDF

Info

Publication number
WO2021078937A1
WO2021078937A1 PCT/EP2020/079879 EP2020079879W WO2021078937A1 WO 2021078937 A1 WO2021078937 A1 WO 2021078937A1 EP 2020079879 W EP2020079879 W EP 2020079879W WO 2021078937 A1 WO2021078937 A1 WO 2021078937A1
Authority
WO
WIPO (PCT)
Prior art keywords
stat3
iron chelator
prodrug
pharmaceutically compatible
subject
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2020/079879
Other languages
English (en)
Inventor
Felix Hoppe-Seyler
Karin Hoppe-Seyler
Tobias Strobel
Anja HERMANN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Deutsches Krebsforschungszentrum DKFZ
Original Assignee
Deutsches Krebsforschungszentrum DKFZ
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Deutsches Krebsforschungszentrum DKFZ filed Critical Deutsches Krebsforschungszentrum DKFZ
Publication of WO2021078937A1 publication Critical patent/WO2021078937A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/345—Nitrofurans
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to a pharmaceutically compatible iron chelator or prodrug thereof for use in treating and/or preventing a disease caused or aggravated by STAT3 hyperactivity in effector cells in a subject; and to methods, kits, devices, uses, and combined preparations related thereto.
  • a common dogma of cancer physiology is that cancer cells exhibit higher intracellular iron levels than normal cells, which is believed to facilitate both initiation and growth of a tumor (Torti and Torti (2013), Nat Rev Cancer 13(5):342).
  • intracellular iron induces the production of reactive oxygen species and therefore increased iron levels can facilitate the initiation of a tumor (Wans & Ahsan (2006), Journal of Carcinogenesis 5:14).
  • cancer cells strongly depend on the activity of the iron dependent enzyme ribonucleotide reductase, which is necessary for DNA synthesis and thus proliferation (Sanvisens et al. (2013), Biomed J 36(2):51-8).
  • iron-dependent enzymes have been implicated in the cancer-promoting effect of iron, e.g. Deoxyhypusine Hydroxylase (Clement et al. (2002), Int J. Cancer, 100:491), or Wnt-Signaling (Song et al. (2011), Cancer Res. 71:7628).
  • Ciclopirox is clinically used as a topical antifungal agent to treat mycoses of the skin and nails. Although its exact mechanism of action is unclear, it is known to chelate intracellular iron (Shen & Huang (2016), Curr Pharm Des 22:4443) and anti-tumor properties have been reported (Zhou et al .(2010), Journal international du cancer 127(10):2467; Eberhard et al. (2009), Blood 114(14):3064). Recently, it was found that ciclopirox can induce senescence and apoptosis in human papillomavirus-positive cancer cells (Braun et al. (2019), Int J Cancer, doi: 10.1002/ijc.32709).
  • STAT3 signaling cascade is considered pro-tumorigenic under most conditions and is hyperactivated in over 70% of all cancers. Many efforts have been undertaken to therapeutically block STAT3 for clinical cancer therapy, however, with only limited success. STAT3 is considered a therapeutic target also for cancers which are often accessible from the outside, such as squamous cell carcinomas of the skin or malignant melanoma. Moreover, STAT3 is also considered a therapeutic target for common non-malignant diseases, such as autoimmune disorders, asthma, cachexia, and fibrotic diseases. Moreover, STAT3 was reported to be a target for cancer prevention (Peyser et al (2016), Cancer Prev Res 9(8):657).
  • the present invention relates to a pharmaceutically compatible iron chelator or prodrug thereof for use in treating and/or preventing a disease caused or aggravated by STAT3 hyperactivity in effector cells in a subject.
  • the terms “have”, “comprise” or “include” or any arbitrary grammatical variations thereof are used in a non-exclusive way. Thus, these terms may both refer to a situation in which, besides the feature introduced by these terms, no further features are present in the entity described in this context and to a situation in which one or more further features are present.
  • the expressions “A has B”, “A comprises B” and “A includes B” may both refer to a situation in which, besides B, no other element is present in A (i.e. a situation in which A solely and exclusively consists of B) and to a situation in which, besides B, one or more further elements are present in entity A, such as element C, elements C and D or even further elements.
  • the expressions “comprising a” and “comprising an” preferably refer to “comprising one or more", i.e. are equivalent to "comprising at least one”.
  • standard conditions if not otherwise noted, relates to IUPAC standard ambient temperature and pressure (SATP) conditions, i.e. preferably, a temperature of 25°C and an absolute pressure of 100 kPa; also preferably, standard conditions include a pH of 7.
  • SATP standard ambient temperature and pressure
  • the term “about” relates to the indicated value with the commonly accepted technical precision in the relevant field, preferably relates to the indicated value ⁇ 20%, more preferably ⁇ 10%, most preferably ⁇ 5%.
  • the term “essentially” indicates that deviations having influence on the indicated result or use are absent, i.e. potential deviations do not cause the indicated result to deviate by more than ⁇ 20%, more preferably ⁇ 10%, most preferably ⁇ 5%.
  • compositions defined using the phrase “consisting essentially of’ encompasses any known acceptable additive, excipient, diluent, carrier, and the like.
  • a composition consisting essentially of a set of components will comprise less than 5% by weight, more preferably less than 3% by weight, even more preferably less than 1%, most preferably less than 0.1% by weight of non-specified component(s).
  • iron chelator relates to a chemical compound forming a stable complex with iron ions, preferably Fe 2+ and/or Fe 3+ .
  • the iron chelator is a compound having a log stability constant for at least one of its iron complexes of at least 3, more preferably at least 5, more preferably 10, still more preferably at least 20, even more preferably at least 25, most preferably at least 30.
  • the log stability constant is the log of the equilibrium constant for the formation of the Fe/iron chelator complex in aqueous solution, preferably determined under standard conditions, preferably as specified elsewhere herein; preferably, the log stability constant of an iron chelator is determined in a solution consisting of water, iron ions, and iron chelator.
  • Iron chelators are, in principle, known in the art and include compounds comprising at least one of a 2-pyridone structure, a hydroxamate structure, a (thio)semicarbazone structure, a bis(2-hydroxyphenyl)-lH-l,2,4-triazol structure, an alpha-hydroxyketone structure, an arylhydrazone structure, and a catechol structure.
  • a pharmaceutically compatible compound relates to a chemical compound which is pharmaceutically acceptable in the sense of being not deleterious to the recipient thereof and, preferably, being compatible with optional other ingredients of a formulation thereof.
  • a pharmaceutically compatible compound is a compound causing at most moderate adverse drug reactions, preferably causing at most mild adverse drug reactions.
  • mild adverse reactions relates to adverse reactions not requiring medical intervention, such as skin rashes, headaches, digestive disturbances, fatigue, and the like; “moderate” adverse reactions are adverse reactions requiring medical intervention, but not being potentially life threatening.
  • a "pharmaceutically compatible iron chelator” is an iron chelator as specified herein above which is pharmaceutically compatible as specified above.
  • the pharmaceutically compatible iron chelator is an iron chelator comprising a chemical compound in clinical use, preferably approved for clinical use by at least one of the Food and Drug Admininstration (FDA), the European Medicines Agency (EMEA), and the Bundesinstitut fiir Arzneistoff und Kunststoff area (BfArM).
  • the pharmaceutically compatible iron chelator is an iron chelator comprising a chemical compound in clinical use as an iron chelator, preferably approved for clinical use by at least one of the aforesaid institutions.
  • the iron chelator is ciclopirox (2(1H)- Pyridinone, 6-cyclohexyl-l-hydroxy-4-methylpyridin-2(lH)-one; CAS-No: 29342-05-0), Deferoxamine (DFO, CAS No. 70-51-9) or hydroxycarbamide (CAS No. 127-07-1, nitrofural (CAS No. 59-87-0), 3-aminopyridine-2-carboxaldehyde Thiosemicarbazone (Triapine, CAS No. 236392-56-6) or 5-Hydroxypyridine-2-carboxaldehyde Thiosemicarbazone (HPCT, CAS No.
  • the pharmaceutically compatible iron chelator is a 2-pyridone derivative and/or a prodrug thereof.
  • prodrug is understood by the skilled person to relate to a compound not having or having only to a reduced extent the relevant activity of being an iron chelator and being converted in the body of a subject to the actual active compound.
  • a prodrug is an ether or preferably an ester of the iron chelator. More preferably, the prodrug is a glycosylate, a phosphate, a sulphate, or a macromolecule-conjugated, e.g. polyethyleneglycol (PEG) conjugated, derivative of the iron chelator.
  • PEG polyethyleneglycol
  • 2-pyridone derivative relates to a compound comprising, at least in a tautomeric form, a Pyridin-2(lH)-one structure. More preferably, the 2-pyridone derivative is a chemical compound comprising a l-Hydroxy-Pyridin-2(lH)-one structure. More preferably, the 2-pyridone derivative is a compound comprising structure (I) with n being 0, 1, 2, 3, 4, 5, or 6;
  • R 1 being H, an optionally substituted carbonyl, optionally substituted phosphoryl, or optionally substituted sulfonyl;
  • R 2 to R 5 being independently selected from -H, an optionally substituted organic side chain, and halogen.
  • side chain is understood by the skilled person and relates to an atom or chemical group attached covalently to the core part of a chemical compound as described herein, said core part also being referred to as "main chain” or "backbone".
  • the side chain is an organic side chain as described herein below.
  • substituted side chain relates to a side chain substituted at one or more positions, preferably, at 1, 2, or 3 positions, wherein substituents may be attached at any available atom to produce a stable chemical compound. It is understood by the skilled person that the term “optionally substituted” side chain relates to an unsubstituted or to a substituted side chain.
  • organic side chain relates to any, optionally substituted, side chain comprising at least one carbon atom.
  • the organic side chain is an, optionally substituted, alkyl, alkenyl, alkinyl, aryl, aralkyl, cycloalkyl, heterocycloalkyl, or heteroaryl side chain.
  • the alkyl, aryl, and aralkyl groups of the substituents are not further substituted by groups comprising alkyl, alkenyl, alkinyl, aryl, aralkyl, heterocycloalkyl, or heteroaryl groups. More preferably, the alkyl, aryl, and aralkyl groups of the substituents are not further substituted.
  • the organic side chain has of from 1 to 10 , more preferably of from 1 to 8, still more preferably of from 1 to 6, even more preferably of from 1 to 5, most preferably of from 1 to 4 C-atoms, preferably including any optional substituents.
  • alkyl relates to a straight or branched chain, saturated hydrocarbon group, linked to the main chain by a covalent bond to at least one of its at least one carbon atoms.
  • Preferred alkyl groups are straight chain alkyls, e.g., preferably, methyl, ethyl, propyl, butyl, pentyl, hexyl, or branched chain alkyl groups, e.g., preferably,
  • alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.
  • cycloalkyl relates to a circularly closed, hydrocarbon group, preferably with 5 to 8 carbon atoms.
  • Preferred cycloalkyls are cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • alkinyl side chain relates to a side chain comprising at least one CoC triple bond linked to the main chain by a covalent bond to at least one of its at least two carbon atoms.
  • cycloalkinyl relates to a circularly closed hydrocarbon group, preferably with 8 to 12 carbon atoms, comprising at least one CoC triple bond and linked to the main chain by a covalent bond to at least one of its at least two carbon atoms.
  • alkoxy side chain relates to an -O-alkyl side chain, preferably having the indicated number of carbon atoms.
  • the alkoxy side chain is -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-sec-butyl, -O-tert-butyl, -O-pentyl, -O- isopentyl, -O-neopentyl, -O-hexyl, -O- isohexyl, or -O-neohexyl.
  • aryl as used herein, relates to an aromatic ring or ring system having 6 to 14 carbon atoms, preferably comprising one, two, or three aromatic rings. Preferred aryl side chains are phenyl, naphthyl, anthracenyl, and phenanthrenyl.
  • ring in the context of the chemical compounds of the present invention, is understood by the skilled person; accordingly, the term “ring system” relates to a chemical structure comprising at least two rings sharing at least one covalent bond.
  • aryl also includes aromatic ring systems fused with a cycloalkyl and/or a heterocycloalkyl ring.
  • aralkyl relates to an alkyl side chain, wherein at least one hydrogen is replaced by an aryl side chain.
  • aralkyl is benzyl or phenethyl.
  • heterocycloalkyl relates to a saturated or partially unsaturated ring or ring system having 5 to 14 ring atoms, preferably 5 to 7 ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of N, O, and S, said ring or ring system being linked to the main chain by a covalent bond to a C or N atom of said ring or ring system.
  • heterocycloalkyl is azepinyl, dihydrofuryl, dihydropyranyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, thiadiazolylidinyl, thiazolidinyl, or thiomorpholinyl.
  • heteroaryl relates to an aromatic ring or ring system having 5 to 14 ring atoms, preferably 5 to 7 ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of N, O, and S, said ring or ring system being linked to the main chain by a covalent bond to a C or N atom of said ring or ring system.
  • up to 4 more preferably up to 3, most preferably up to 2 ring atoms per ring are heteroatoms independently selected from the group of heteroatoms consisting of N, O, and S.
  • heteroaryl is pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, or indolyl.
  • the pharmaceutically compatible iron chelator is a compound comprising structure (I), with n being 0, 1, 2, 3, 4, 5, or 6; R 1 being H, an optionally substituted carbonyl, optionally substituted phosphoryl, or optionally substituted sulfonyl; and R 2 to R 5 being independently selected from -H, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl aralkyl, heterocycloalkyl, heteroaryl, and halogen.
  • the pharmaceutically compatible iron chelator is a compound comprising structure (I), with n being 0, 1, 2, 3, 4, 5, or 6; R 1 being H, optionally substituted carbonyl, optionally substituted phosphoryl, or optionally substituted sulfonyl; R 2 being selected from cyclohexyl, -H, C 1 -C 6 alkyl, Cs-Cx cycloalkyl, C 1 -C 6 alkoxy, and halogen; R 4 being selected from methyl, -H, C 1 -C 6 alkyl, Cs-Cx cycloalkyl, C 1 -C 6 alkoxy, and halogen; and R 3 and R 5 being independently selected from -H, C 1 -C 6 alkyl, Cs-Cx cycloalkyl, C 1 -C 6 alkoxy, and halogen.
  • R 1 being H, optionally substituted carbonyl, optionally substituted phosphoryl, or optionally substituted sulfonyl
  • STAT3 is understood by the skilled person to relate to a member of the “signal transducer and activator of transcription” (STAT) family of proteins known under this designation, including its isoforms, such as splice variants.
  • STAT3 is mammalian STAT3, more preferably human STAT3.
  • the gene and the polypeptide sequence of human STAT3 are known to the skilled person; e.g. human isoform 1 has the amino acid sequence as shown in Genbank Acc. No. NP_644805.1.
  • Antibodies to STAT3 are commercially available, as also referred to herein in the Examples.
  • STAT3 target genes are known, e.g. from Carpenter & Lo (2014) Cancers (Basel) 6(2):897).
  • the skilled person is well able to determine STAT3 expression, in particular its polypeptide levels, and STAT3 activity in a biological sample.
  • STAT3 activity is used herein in its usual meaning known to the skilled person to relate to the activity of STAT3 as a transcriptional regulator; as indicated above, STAT3 target genes are known in the art, thus the skilled person is able to determine STAT3 activity.
  • STAT3 hyperactivity relates to an increased activity of STAT3 in an effector cell, preferably exceeding STAT3 activity in a corresponding normal cell, preferably by at least a factor 2, more preferably at least a factor of 3, still more preferably at least a factor of five, most preferably at least a factor of ten.
  • corresponding normal cells are cells of the same type from a subject or a group of subjects not suffering from a disease as specified herein; corresponding normal cells may, however, also be derived from the same subject but from a sample known not to be affected by STAT3 hyperactivity.
  • STAT3 hyperactivity is determined as STAT3 overexpression compared to a corresponding normal cell, preferably by at least a factor 2, more preferably at least a factor of 3, still more preferably at least a factor of five, most preferably at least a factor of ten, at the polypeptide level.
  • STAT3 hyperactivity is determined as increased amount of STAT3 phosphorylated at a position corresponding to Tyrosine 705 of the amino acid sequence of human STAT3 compared to a corresponding normal cell, preferably by at least a factor 2, more preferably at least a factor of 3, still more preferably at least a factor of five. Also preferably, STAT3 hyperactivity is determined as increased amount of STAT3 phosphorylated at a position corresponding to Serine 727 of the amino acid sequence of human STAT3 compared to a corresponding normal cell, preferably by at least a factor 2, more preferably at least a factor of 3, still more preferably at least a factor of five.
  • STAT3 hyperactivity and/or overexpression is determined in comparison to a reference; preferably, as detailed herein above, said reference provided from corresponding normal cells.
  • the reference is a standard cultured cell, more preferably HeLa cells, still more preferably SiHa cells.
  • the term "effector cell” relates to a cell causing or contributing to a disease as specified herein and showing hyperactivation of STAT3.
  • the effector cell is a cell causing or aggravating an immune hyperactivation, preferably causing and/or aggravating autoimmune disease and/or lymphoproliferative disease.
  • the effector cell is an immune cell, preferred immune cells being T-cells, B-cells, NK cells, and dendritic cells.
  • the effector cell may, however, also be any other cell contributing to a disease as specified, e.g. a skin cell in psoriasis.
  • the effector cell is a cancer cell or a precancerous lesion cell.
  • the cancer cell is a papillomavirus (PV)-infected cell, in particular a human papillomavirus (HPV)-infected cell, preferably a PV- or HPV-infected cancer or precancerous lesion cell.
  • the effector cells are cells of the growth and invasion rim of a tumor, preferably of an HPV positive tumor.
  • the effector cells is an HPV-negative cell, more preferably a PV-negative cell.
  • the term "disease caused or aggravated by STAT3 hyperactivity in effector cells”, as used herein, relates to any disease or disorder having the aforesaid cause.
  • Corresponding diseases are known in the art.
  • the disease caused or aggravated by STAT3 hyperactivity in effector cells is cancer, preferably cancer in which the cancer cells are suspected or known, preferably are known, to comprise STAT3 hyperactivity, preferably overexpress STAT3.
  • the disease caused or aggravated by STAT3 hyperactivity in effector cells is an immune hyperactivation, preferably an autoimmune disease and/or a lymphoproliferative disease; more preferably psoriasis, inflammatory bowel diseases (e. g.
  • the disease caused or aggravated by STAT3 hyperactivity in effector cells is asthma.
  • the disease caused or aggravated by STAT3 hyperactivity in effector cells is cachexia.
  • the disease caused or aggravated by STAT3 hyperactivity in effector cells is a fibrotic disease, such as lung fibrosis, liver fibrosis, or scleroderma. Symptoms and methods for the diagnosis of the aforesaid diseases caused or aggravated by STAT3 hyperactivity in effector cells are known to the skilled person and can be derived from standard medical textbooks.
  • the disease caused or aggravated by STAT3 hyperactivity in effector cells is STAT3 gain-of-function disease, a hereditary, autosomal dominant disease.
  • the disease caused or aggravated by STAT3 hyperactivity in effector cells is not an HPV-related disease, more preferably not a PV-related disease.
  • cancer is, in principle, understood by the skilled person and relates to a disease of an animal, including man, characterized by uncontrolled growth by a group of body cells (“cancer cells”). This uncontrolled growth may be accompanied by intrusion into and destruction of surrounding tissue and possibly spread of cancer cells to other locations in the body.
  • tumor recurrence i.e. relapse.
  • the cancer is a solid cancer, i.e. a cancer forming at least one detectable tumor, a metastasis, or a relapse thereof.
  • the cancer is a non-solid cancer.
  • the cancer cells are effector cells as specified elsewhere herein, i.e., preferably, comprise an increased activity of STAT3 and/or overexpress STAT3.
  • the cancer is selected from the list consisting of aids-related lymphoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, brain stem glioma, breast cancer, burkitt lymphoma, carcinoid tumor, cerebellar astrocytoma, cervical cancer, chordoma, colon cancer, colorectal cancer, craniopharyngioma, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal strom
  • treating refers to an amelioration of the diseases or disorders referred to herein or the symptoms accompanied therewith to a significant extent. Said treating as used herein also includes an entire restoration of health with respect to the diseases or disorders referred to herein. It is to be understood that treating, as the term is used herein, may not be effective in all subjects to be treated. However, the term shall require that, preferably, a statistically significant portion of subjects suffering from a disease or disorder referred to herein can be successfully treated.
  • Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student's t-test, Mann- Whitney test etc..
  • Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99 %.
  • the p-values are, preferably, 0.1, 0.05, 0.01, 0.005, or 0.0001.
  • the treatment shall be effective for at least 10%, at least 20% at least 50% at least 60%, at least 70%, at least 80%, or at least 90% of the subjects of a given cohort or population.
  • treating cancer is reducing tumor burden in a subject.
  • treating causes effector cells to undergo senescence or apoptosis.
  • treating has the effect of causing a tumor to stop growing, more preferably to cause regression of a tumor, more preferably of causing a tumor to resolve.
  • the above relates to treating a HPV-related lesion mutatis mutandis.
  • preventing refers to retaining health with respect to the diseases or disorders referred to herein for a certain period of time in a subject. It will be understood that the said period of time may be dependent on the amount of the drug compound which has been administered and individual factors of the subject discussed elsewhere in this specification. It is to be understood that prevention may not be effective in all subjects treated with the compound according to the present invention. However, the term requires that, preferably, a statistically significant portion of subjects of a cohort or population are effectively prevented from suffering from a disease or disorder referred to herein or its accompanying symptoms. Preferably, a cohort or population of subjects is envisaged in this context which normally, i.e. without preventive measures according to the present invention, would develop a disease or disorder as referred to herein.
  • treating and/or preventing comprises topical application of the pharmaceutically compatible iron chelator, preferably to a mucosa, a skin, and/or a joint, preferably to a mucosa and/or a skin.
  • treating and/or preventing cancer comprises inducing an irreversible proliferation arrest in a cancer cell, which may, preferably, proceed to cell death, in particular apoptosis, under prolonged treatment and/or increased dose of iron chelator.
  • the term "irreversible proliferation arrest”, as used herein, relates to all states of a cell in which no further cell division occurs.
  • the irreversible proliferation arrest is a cell death mechanism and/or senescence, more preferably is senescence, in a preferred embodiment is apoptosis.
  • Cell death mechanisms are known to the skilled person and include in particular apoptosis, mitotic catastrophe, autophagy, and necrosis. As used herein, the above relates to treating and/or preventing a HPV-related lesion mutatis mutandis.
  • the treatment further comprises administration of an immunomodulatory agent.
  • Immunomodulatory agents are described elsewhere herein.
  • the treatment further comprises administration of anticancer treatment as specified elsewhere herein, more preferably of chemotherapy and/or radiotherapy.
  • the effector cell is a PV positive cell, preferably a HPV positive cell
  • treating and/or preventing comprises preventing malignant transformation of a precancerous lesions.
  • the precancerous lesion is a histological cervical intraepithelial neoplasia (CIN) 1, CIN 2, or CIN 3, more preferably CIN 2 or CIN 3 lesion.
  • the iron chelator or prodrug thereof may in particular be administered to a site of a precancerous lesion, preferably a mucosa, more preferably cervical mucosa or oropharyngeal mucosa.
  • the effector cell is a PV positive cell, preferably a HPV positive cell
  • treating and/or preventing comprises preventing tissue invasion. Since it was found in the work underlying the present invention that in HPV positive tumors STAT3 is in particular overexpressed in cells forming the outer shell of the tumor, in such case the cells forming this outer shell preferably are effector cells.
  • the effector cell is a PV positive cell, preferably a HPV positive cell
  • treating comprises avoiding concurrent apoptosis-inducing treatment and treatment with a pharmaceutically compatible iron chelator; in such case, it is preferred that treatment with an iron chelator is administered before or after apoptosis-inducing treatment.
  • the time span between apoptosis-inducing treatment and iron-chelator treatment in such case is at least 1 day, more preferably at least 3 days, more preferably at least one week, most preferably at least two weeks.
  • apoptosis-inducing treatment is used herein in its usual meaning and preferably relates to any treatment causing at least a fraction of effector cells to undergo apoptosis, preferably at least 10%, more preferably at least 25%, still more preferably at least 50%, most preferably at least 75% of effector cells.
  • the apoptosis-inducing treatment is an anticancer treatment as specified elsewhere herein, more preferably is chemotherapy and/or radiotherapy.
  • the term "immunomodulatory agent” is used herein in a broad sense for all agents having the activity of causing the immune system of a subject to be modulated, i.e. to be repressed or activated, preferably repressed, preferably to a significant extent.
  • the term includes all physical, chemical, and biological agents having the aforesaid effect.
  • the immunomodulatory agent preferably is a physical agent, more preferably radiation, still more preferably ultraviolet (UV) radiation or infrared (IR) radiation, heat, or cold, most preferably is UV radiation.
  • the immunomodulatory agent is a chemical agent, in particular a corticosteroid, a non-steroidal anti-inflammatory drug, vitamin D or an analogue thereof, a retinoid, a calcineurin inhibitor, or cyclosporine.
  • the immunomodulatory agent is a biological agent, in particular etanercept, infliximab, adalimumab, ustekinumab, golimumab, apremilast, secukinumab, or ixekizumab; or an agent comprising immunomodulatory cells or mixtures thereof such as regulatory T-cells, a cytokine, or a checkpoint inhibitor, e.g. targeting CTLA4, PD-1, and/or PD-L1.
  • anticancer treatment relates to measures administered to a subject to remove cancer cells from the subject, to kill cancer cells in the subject, to inhibit growth of cancer cells in the subject, and/or to cause the body of the subject to inhibit growth of or to kill cancer cells.
  • anticancer treatment preferably comprises surgery, radiotherapy, chemotherapy, anti-hormone therapy, targeted therapy, and/or cancer immunotherapy.
  • anticancer treatment comprises surgery; more preferably, anticancer treatment comprises surgery and radiotherapy; still more preferably, anticancer treatment comprises surgery, radiotherapy, and chemotherapy.
  • Anticancer treatment may in principle be administered before, simultaneously to, and/or after preventing administration of an iron chelator or a prodrug thereof.
  • chemotherapy relates to treatment of a subject with an antineoplastic drug.
  • chemotherapy is a treatment including alkylating agents (e.g. cyclophosphamide), platinum (e.g. carboplatin), anthracyclines (e.g. doxorubicin, epirubicin, idarubicin, or daunorubicin) and topoisomerase II inhibitors (e.g.
  • etoposide, irinotecan, topotecan, camptothecin, or VP 16 anaplastic lymphoma kinase (ALK)-inhibitors (e.g. Crizotinib or AP26130), aurora kinase inhibitors (e.g. N-[4-[4-(4-Methylpiperazin-l-yl)-6-[(5-methyl-lH-pyrazol-3-yl)amino]pyrimidin-2- yl]sulfanylphenyl]cyclopropanecarboxamide (VX-680)), antiangiogenic agents (e.g.
  • ALK aplastic lymphoma kinase
  • aurora kinase inhibitors e.g. N-[4-[4-(4-Methylpiperazin-l-yl)-6-[(5-methyl-lH-pyrazol-3-yl)amino]pyrimidin-2-
  • chemotherapy preferably, relates to a complete cycle of treatment, i.e. a series of several (e.g. four, six, or eight) doses of antineoplastic drug or drugs applied to a subject separated by several days or weeks without such application.
  • anti-hormone therapy relates to cancer therapy by blocking hormone receptors, e.g. estrogen receptor or progesterone receptor, expressed on cancer cells, or by blocking the biosynthesis of a hormone the cancer is dependent on.
  • Blocking of hormone receptors can preferably be achieved by administering compounds, e.g. tamoxifen, binding specifically and thereby blocking the activity of said hormone receptors.
  • Blocking of hormone biosynthesis is preferably achieved by administration of inhibitors, e.g. in the case of estrogen, aromatase inhibitors like, e.g. anastrozole or letrozole may be used.
  • inhibitors e.g. in the case of estrogen, aromatase inhibitors like, e.g. anastrozole or letrozole may be used.
  • anti-hormone therapy is preferably advisable in cases where tumor cells are expressing hormone receptors.
  • targeted therapy as used herein, relates to application to a patient of a chemical substance known to block growth of cancer cells by interfering with specific molecules known to be necessary for tumorigenesis or cancer or cancer cell growth.
  • cancer immunotherapy relates to the treatment of cancer by modulation of the immune response of a subject. Said modulation may be inducing, enhancing, or suppressing said immune response.
  • cell based immunotherapy relates to a cancer therapy comprising application of immune cells, e.g. T-cells, preferably tumor-specific NK cells, to a subject.
  • cancer immunotherapy which aims at inhibiting or killing cancer cells, has a purpose different from treatment with an immunomodulatory agent as specified herein above, which aims at preventing a further immune overstimulation and the detrimental consequences thereof to a subject; nonetheless, the same or similar agents may be used in both treatments.
  • subject relates to a multicellular animal, preferably to a vertebrate, more preferably to a mammal. More preferably, the subject is a human, a cattle, a pig, a sheep, a goat, a horse, a cat, a dog, a guinea pig, a mouse, or a rat.
  • the subject is a laboratory animal, preferably a guinea pig, a mouse, or a rat.
  • the subject is a livestock, preferably a cattle, a pig, a sheep, a goat, or a horse.
  • the subject is a companion animal, preferably a cat, a dog, or a guinea pig.
  • the subject is a human.
  • the subject is known or suspected to suffer from a disease caused or aggravated by STAT3 hyperactivity, preferably cancer, an immune hyperactivation disease, preferably auto immune disease, and/or STAT3 gain-of function disease.
  • the subject was identified to profit from treatment with a pharmaceutically compatible iron chelator by the method according to the present invention.
  • the iron chelator or prodrug thereof is comprised in a composition.
  • composition relates to a mixture of compounds comprising at least a compound as specified herein and, preferably, at least one carrier.
  • the compounds, preferably the iron chelator or prodrug thereof, comprised in the composition are described herein above.
  • the composition may have any consistency deemed appropriate by the skilled person.
  • the composition is a solid composition, e.g. a tablet or a powder, a semisolid composition, e.g. a gel, or, more preferably, a liquid, e.g. a solution or an emulsion.
  • the composition preferably comprises a carrier.
  • the carrier(s) preferably is/are acceptable in the sense of being compatible with the other ingredients of the composition and being not deleterious to a potential recipient thereof.
  • the carrier(s) preferably is/are selected so as not to affect the biological activity of the composition.
  • the composition is sterile, more preferably a sterile solution, most preferably a sterile solution for injection.
  • the carrier is selected by the skilled person such as to achieve the consistency intended and may be, for example, a gel or, preferably, a liquid, more preferably an aqueous liquid.
  • Such carriers are distilled water, physiological saline, Ringer's solutions, dextrose solution, phosphate-buffered saline solution, and Hank's solution.
  • the carrier may include one or more solvents or other ingredients increasing solubility of the compounds comprised in the composition.
  • Further examples of liquid carriers are syrup, oil such as peanut oil and olive oil, water, emulsions, various types of wetting agents, sterile solutions and the like. Suitable carriers comprise those mentioned above and others well known in the art.
  • the composition in particular the pharmaceutical composition, may comprise one or more further compounds; preferably, such additional compounds are selected so as to not affect the biological activity of the composition, in particular of the active compounds, such as the iron chelator, and/or is acceptable in the sense of being compatible with the other ingredients of the composition and being not deleterious to a potential recipient thereof.
  • additional compounds are selected so as to not affect the biological activity of the composition, in particular of the active compounds, such as the iron chelator, and/or is acceptable in the sense of being compatible with the other ingredients of the composition and being not deleterious to a potential recipient thereof.
  • the composition according to the present specification is a pharmaceutical composition; thus, preferably, the carrier is a pharmaceutically acceptable carrier.
  • the pharmaceutical composition or formulation may also include other carriers, adjuvants, stabilizers and/or other compounds deemed appropriate by the skilled person, e.g. for galenic purposes.
  • the compound as specified herein above, in particular the iron chelator or prodrug thereof as specified is the "active compound" of the preparation, although "further active compounds", which are referred to under this term, may be present.
  • the active compound and the further active compound i.e. preferably the active compounds, are pharmaceutically active compounds.
  • compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound referred to herein above, preferably in admixture or otherwise associated with at least one pharmaceutically acceptable carrier or diluent.
  • the active compound(s) will usually be mixed with a carrier or the diluent.
  • the resulting formulations are to be adapted to the mode of administration, i.e. in the forms of tablets, capsules, suppositories, solutions, suspensions or the like. Dosage recommendations shall be indicated in the prescriber's or user's instructions in order to anticipate dose adjustments depending on the considered recipient.
  • the pharmaceutical composition is, preferably, administered systemically or, more preferably, topically.
  • Suitable routes of administration conventionally used for drug administration are topical, intravenous, or parenteral administration as well as inhalation.
  • administration is systemic, more preferably intravenous.
  • the pharmaceutical composition may be administered by other routes as well.
  • the pharmaceutical composition may be administered topically, e.g. as a tablet, in particular as a time-delay preparation, which is preferably implanted during surgery removing a tumor, or e.g. as a gel administered to a mucosa.
  • Other modes of administration are specified elsewhere herein.
  • the pharmaceutical composition can be administered in combination with other further active compounds either in a common pharmaceutical composition or as separated pharmaceutical compositions wherein said separated pharmaceutical compositions may be provided in form of a kit of parts.
  • the pharmaceutical composition is, preferably, administered in conventional dosage forms prepared by combining the active compound with standard pharmaceutical carriers according to conventional procedures. These procedures may involve mixing or dissolving the ingredients as appropriate to obtain the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. Similarly, the carrier or diluent may include time delay material well known in the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
  • a therapeutically effective dose refers to an amount of the active compound to be used in a pharmaceutical composition of the present invention which provides the effect referred to in this specification.
  • Therapeutic efficacy and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
  • the dosage regimen will be determined by the attending physician and other clinical factors; preferably in accordance with any one of the above described methods. As is well known in the medical arts, dosages for any one patient depend upon many factors, which may include the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. Progress can be monitored by periodic assessment.
  • a typical dose can be, for example, in the range of 1 pg to 1000 mg; however, doses below or above this exemplary range are envisioned, especially considering the aforementioned factors.
  • the regimen as a regular administration of the pharmaceutical composition should be in the range of 1 pg to 100 mg units per day. If the regimen is a continuous infusion, it should also be in the range of 1 pg to 1 mg units per kilogram of body weight per minute, respectively.
  • the pharmaceutical composition is administered once to the subject, i.e., preferably, is used as a one-time treatment.
  • the quantity of substance administration may vary over a wide range to provide from about 0.01 mg per kg body mass to about 100 mg per kg body mass.
  • compositions and formulations referred to herein are administered at least once in order to treat or ameliorate or prevent a disease or condition recited in this specification.
  • the said pharmaceutical compositions may be administered more than one time, for example from two to 50 times, more preferably from five to 50 times.
  • administration is adjusted to maintain an effective concentration in the body of a subject for the time period intended.
  • the pharmaceutical preparation may be administered topically at the site of a tumor as a depot; in such case, the depot preferably is adjusted to maintain an effective dose until at least after additional cancer treatment, e.g. chemotherapy, was administered or, preferably, until such additional cancer treatment has been completed. Progress can be monitored by periodic assessment.
  • iron chelators are effective in inducing STAT3 degradation in living cells and in ameliorating or preventing the effects of STAT3 hyperactivation.
  • the present invention further relates to a method for identifying a subject profiting from treatment with an iron chelator, comprising
  • the method of the present invention preferably, is an in vitro method. Moreover, it may comprise steps in addition to those explicitly mentioned above. For example, further steps may relate, e.g., to pre-processing a sample for step a), e.g. by fixing and embedding, or comparing the STAT3 activity and/or expression determined in step a) to a reference in step b). Moreover, one or more of said steps may be performed by automated equipment.
  • the term "profiting from treatment with an iron chelator”, as used herein, relates to an improvement of health and/or of survival probability by iron chelator treatment. It is to be understood that profiting from treatment with an iron chelator may not be effective in all subjects treated. However, the term preferably requires that improvement of health and/or survival is observed for a statistically significant portion of subjects of a cohort or population. Preferably, a cohort or population of subjects is envisaged in this context which normally, i.e. without iron chelator treatment, would develop the adverse health-related event, would develop more severe adverse health-related events, and/or would show increased mortality. Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, preferably as specified elsewhere herein.
  • STAT3 activity is preferably determined e.g. in a reporter gene assay, preferably using one of the known STAT3 regulated genes; STAT3 expression is preferably determined as STAT3, more preferably P-STAT3, polypeptide levels, which are preferably determined by immunological methods, preferably using STAT3- or P-STAT3- specific antibodies, but may also be determined by other methods, e.g. by mass spectrometry.
  • STAT3 activity and/or amount of STAT3 gene product determined is compared to a reference; suitable references have been described herein above.
  • STAT3 hyperactivity and/or overexpression is determined in case STAT3 activity and/or the amount of STAT3 gene product is found increased compared to a reference.
  • STAT3 expression levels can be used as a surrogate marker of STAT3 activity; thus, it is preferably not always required to determine STAT3 activity as such.
  • sample refers to any sample suspected or known to comprise effector cells; thus, the sample preferably is a biological sample.
  • the sample is a sample of a body fluid, a sample of separated cells, a sample from a tissue or an organ, or a sample of wash/rinse fluid obtained from an outer or inner body surface of a subject.
  • the sample is a body fluid like blood, plasma, serum, urine, saliva, or lacrimal fluid.
  • the sample is a tissue sample, more preferably a tumor tissue or inflammation tissue sample, known or suspected to comprise effector cells. Samples can be obtained by well-known techniques which include, preferably, scrapes, swabs or biopsies.
  • samples can be obtained by use of brushes, (cotton) swabs, spatula, rinse/wash fluids, punch biopsy devices, puncture of cavities with needles or by surgical instrumentation.
  • the sample is a biopsy, a tumor, or part thereof.
  • Separated cells and/or cell-free liquids may be obtained from cell culture supernatants, body fluids, or the tissues or organs by separating techniques such as filtration, centrifugation, or cell sorting. It is to be understood that the sample may be further processed in order to carry out a method of the present invention.
  • the present invention also relates to a method for treating a disease caused or aggravated by STAT3 overexpression in effector cells in a subject suffering therefrom, comprising
  • the method for treating of the present invention preferably, is an in vivo method. Moreover, it may comprise steps in addition to those explicitly mentioned above. For example, further steps may relate, e.g., to diagnosing the disease caused or aggravated by STAT3 overexpression and/or identifying the subject as profiting from treatment with an iron chelator, preferably according to the method specified above, before step a); thus, preferably, the method comprises the further steps of (i) determining or having determined STAT3 activity and/or expression in a sample of said subject; and (ii) identifying or having identified a subject profiting from treatment with an iron chelator in case STAT3 hyperactivity and/or overexpression is determined. Also, a further step may comprise co-treating the subject as specified herein above in step b). Moreover, one or more of said steps may be performed by automated equipment.
  • the present invention also relates to a kit comprising an iron chelator or a prodrug thereof and a means of determining STAT3 expression.
  • kit refers to a collection of the aforementioned components. Preferably, said components are combined with additional components, preferably within an outer container. Examples for such components of the kit as well as methods for their use have been given elsewhere in this specification. Suitable means for determining STAT3 expression are known to the skilled person and include in particular a STAT3 -specific antibody, a hybridization probe specific for a STAT3 encoding sequence or part thereof, PCR primers specific for a STAT3 encoding sequence or part thereof, and the like.
  • the kit preferably, contains the aforementioned components in a ready-to-use formulation.
  • the kit preferably comprises further components, preferably a cancer therapeutic agent as specified herein above, a diluent, and/or a means of administration, in particular a syringe and/or a needle, and/or an IV infusion equipment.
  • the kit may additionally comprise instructions, e.g., a user’s manual for carrying out a method of the present invention. Details are to be found elsewhere in this specification. Additionally, such user’s manual may provide instructions about correctly using the components of the kit.
  • a user’s manual may be provided in paper or electronic form, e.g., stored on CD or CD ROM.
  • the present invention also relates to the use of said kit in any of the methods according to the present invention.
  • the present invention further relates to a device comprising (i) an analysis unit comprising a means for determining STAT3 activity and/or expression in a sample, and, operatively connected thereto (ii) an evaluation means comprising tangibly embedded executable instructions for performing a method according to the present invention.
  • means for determining STAT3 activity and/or expression include means capable for determining an amount of STAT3 polypeptide, such as an ELISA reader, means for determining an amount of STAT3 mRNA, such as a quantitative PCR device, or means for determining STAT3 activity, such as an optical unit detecting a signal of a reporter gene assay.
  • An evaluation means is any means capable of providing the analysis as specified; preferably, the evaluation means is a data processing means, such as a microprocessor, a handheld device such as a mobile phone, or a computer. How to link the means in an operating manner will depend on the type of means included into the device.
  • the means are comprised by a single device. Said device may accordingly include (i) an analyzing unit for the measurement of the amount and/or activity of STAT3 in a sample and a (ii) computer unit for processing the resulting data for the evaluation. Typical means for detection are disclosed herein above.
  • the instructions and interpretations are comprised in an executable program code comprised in the device, such that, as a result of determination a classification of the subject as profiting or not profiting from iron chelator treatment may be output to a user.
  • Typical devices are those which can be applied without the particular knowledge of a specialized technician, e.g., test stripes or electronic devices which merely require loading with a sample.
  • the results may be given as output of raw data which need interpretation by a technician.
  • the output of the device is, however, processed, i.e. evaluated, raw data, the interpretation of which does not require a technician.
  • the device further comprises a memory unit, preferably comprising a database comprising at least one reference value for a STAT3 activity and or expression.
  • the present invention also relates to a use of an iron chelator or prodrug thereof for increasing apoptosis sensitivity in a STAT3 -overexpressing cell, preferably a STAT3 overexpressing cancer cell.
  • the term "increasing apoptosis sensitivity" is used herein relative to an otherwise identical STAT3-overexpressing cells, which was not treated with an iron chelator.
  • said use is an in vitro use.
  • the present invention also relates to a combined preparation comprising (i) a pharmaceutically compatible iron chelator or prodrug thereof and (ii) an anticancer agent and/or an immunomodulatory agent for use in treating and/or preventing a disease caused or aggravated by STAT3 overexpression in effector cells in a subject.
  • combined preparation relates to a preparation comprising the pharmaceutically active compounds of the present invention in one preparation.
  • the combined preparation is comprised in a container, i.e. preferably, said container comprises all pharmaceutically active compounds of the present invention.
  • said container comprises the pharmaceutically active compounds of the present invention as separate formulations, i.e. preferably, one formulation of the active compound as specified herein and one formulation of a cancer therapeutic agent and/or an immunomodulatory agent.
  • formulation relates to a, preferably pharmaceutically acceptable, mixture of compounds, comprising or consisting of at least one pharmaceutically active compound.
  • the combined preparation comprises the active compound and the further active compound in a single solid pharmaceutical form, e.g. a tablet or, preferably, a solution; more preferably, the active compounds of the present invention are comprised in two separate, preferably liquid, formulations; said separate liquid formulations, preferably are for injection, preferably at different parts of the body of a subject.
  • the combined preparation is for separate or for combined administration.
  • Separatate administration relates to an administration wherein at least two active compounds are administered via different routes and/or at different parts of the body of a subject. E.g. one compound may be administered by enteral administration (e.g. orally), whereas a second compound is administered by parenteral administration (e.g. intravenously).
  • the combined preparation for separate administration comprises at least two physically separated preparations for separate administration, wherein each preparation contains at least one active or further active compound; said alternative is preferred e.g. in cases where the pharmaceutically active compounds of the combined preparation have to be administered by different routes, e.g. parenterally and orally, due to their chemical or physiological properties.
  • combined administration relates to an administration wherein the active compounds are administered via the same route, e.g. orally or, preferably, intravenously.
  • the combined preparation is for simultaneous or for sequential administration.
  • Simultaneous administration relates to an administration wherein the active compounds are administered at the same time, i.e., preferably, administration of the pharmaceutically active compounds starts within a time interval of less than 15 minutes, more preferably, within a time interval of less than 5 minutes. Most preferably, administration of the pharmaceutically active compounds starts at the same time, e.g.
  • “sequential administration”, as used herein, relates to an administration causing plasma concentrations of the active compounds in a subject enabling the synergistic effect of the present invention, but which, preferably, is not a simultaneous administration as specified herein above.
  • sequential administration is an administration wherein administration of the active compounds, preferably all active compounds, starts within a time interval of 1 or 2 days, more preferably within a time interval of 12 hours, still more preferably within a time interval of 4 hours, even more preferably within a time interval of one hour, most preferably within a time interval of 5 minutes.
  • Embodiment 1 A pharmaceutically compatible iron chelator or prodrug thereof for use in treating and/or preventing a disease caused or aggravated by STAT3 hyperactivity in effector cells in a subject.
  • Embodiment 2 The pharmaceutically compatible iron chelator or prodrug thereof for use of embodiment 1, wherein said pharmaceutically compatible iron chelator comprises at least one of a 2-pyridone structure, a hydroxamate structure, a (thio)semicarbazone structure, a bis(2-hydroxyphenyl)-lH-l,2,4-triazol structure, an alpha-hydroxyketone structure, an arylhydrazone structure, and a catechol structure.
  • Embodiment s The pharmaceutically compatible iron chelator or prodrug thereof for use of embodiment 1 or 2, wherein said pharmaceutically compatible iron chelator is a 2- pyridone derivative and/or a prodrug thereof.
  • Embodiment 4 The pharmaceutically compatible iron chelator or prodrug thereof for use of any one of embodiments 1 to 3, wherein said 2-pyridone derivative and/or prodrug comprises structure with n being 0, 1, 2, 3, 4, 5, or 6;
  • R 1 being H, optionally substituted carbonyl, optionally substituted phosphoryl, or optionally substituted sulfonyl;
  • R 2 being selected from cyclohexyl, -H, C1-C6 alkyl, C5-C8 cycloalkyl, C1-C6 alkoxy, and halogen;
  • R 4 being selected from methyl, -H, C1-C6 alkyl, C5-C8 cycloalkyl, C1-C6 alkoxy, and halogen;
  • R 3 and R 5 being independently selected from -H, C1-C6 alkyl, C5-C8 cycloalkyl, Cl- C6 alkoxy, and halogen.
  • R 1 is H, optionally substituted carbonyl, or optionally substituted phosphoryl
  • R 2 is cyclohexyl
  • R 4 is methyl; and R 3 and R 5 are -H.
  • Embodiment 6 The pharmaceutically compatible iron chelator for use of any one of embodiments 1 to 5, wherein said pharmaceutically compatible iron chelator is ciclopirox (2(lH)-Pyridinone, 6-cyclohexyl- l-hydroxy-4-methylpyridin-2(lH)-one; CAS-No: 29342-05- 0), preferably ciclopirox olamine.
  • Embodiment 7 The pharmaceutically compatible iron chelator for use of embodiment 1 or 2, wherein said pharmaceutically compatible iron chelator is (i) a hydroxamate iron chelator, more preferably Deferoxamine (DFO, CAS No. 70-51-9) or hydroxycarbamide (CAS No. 127-07-1, (ii) a (thio)semicarbazone iron chelator, preferably nitrofural (CAS No. 59-87-0), 3-aminopyridine-2-carboxaldehyde Thiosemicarbazone (Triapine, CAS No. 236392-56-6) or 5-Hydroxypyridine-2-carboxaldehyde Thiosemicarbazone (HPCT, CAS No.
  • a hydroxamate iron chelator more preferably Deferoxamine (DFO, CAS No. 70-51-9) or hydroxycarbamide (CAS No. 127-07-1
  • the pharmaceutically compatible iron chelator or prodrug thereof for use of any one of embodiments 1 to 7, wherein said disease caused or aggravated by STAT3 hyperactivity in effector cells is (i) cancer, (ii) an autoimmune disease, preferably psoriasis, rheumatoid arthritis, or an inflammatory bowel disease, in particular Crohn’s disease or ulcerative colitis; (iii) asthma, (iv) cachexia, or (v) a fibrotic disease, in particular lung fibrosis, liver fibrosis, or scleroderma.
  • Embodiment 9 The pharmaceutically compatible iron chelator or prodrug thereof for use of any one of embodiments 1 to 8, wherein said effector cells are HPV-positive cells.
  • Embodiment 11 The pharmaceutically compatible iron chelator or prodrug thereof for use of embodiment 9 or 10, wherein said treating comprises avoiding concurrent apoptosis- inducing treatment and treatment with a pharmaceutically compatible iron chelator.
  • Embodiment 12 The pharmaceutically compatible iron chelator or prodrug thereof for use of any one of embodiments 1 to 11, wherein said treating and preventing comprises topical administration of said pharmaceutically compatible iron chelator.
  • Embodiment 13 The pharmaceutically compatible iron chelator or prodrug thereof for use of any one of embodiments 1 to 12, wherein said treating and/or preventing further comprises administration of apoptosis-inducing treatment, preferably chemotherapy and/or radiotherapy.
  • Embodiment 14 The pharmaceutically compatible iron chelator or prodrug thereof for use of any one of embodiments 1 to 13, wherein said effector cells are cells causing or aggravating an immune hyperactivation.
  • Embodiment 15 The pharmaceutically compatible iron chelator or prodrug thereof for use of any one of embodiments 1 to 14, wherein said effector cells are cells causing and/or aggravating autoimmune disease and/or lymphoproliferative disease.
  • Embodiment 16 The pharmaceutically compatible iron chelator or prodrug thereof for use of any one of embodiments 1 to 15, wherein said disease is STAT3 gain-of- function disease.
  • Embodiment 17 The pharmaceutically compatible iron chelator or prodrug thereof for use of any one of embodiments 1 to 16, wherein said subject was identified to profit from treatment with a pharmaceutically compatible iron chelator by the method according to any one of embodiments 18 to 20.
  • Embodiment 18 A method for identifying a subject profiting from treatment with an iron chelator, comprising
  • Embodiment 19 The method of embodiment 18, wherein said sample is known or suspected to comprise effector cells.
  • Embodiment 20 The method of embodiment 18 or 19, wherein said method comprises the further step of comparing the STAT3 activity and/or expression determined in step (a) to a reference; and wherein a subject profiting from treatment with an iron chelator is identified in case STAT3 activity and/or expression is higher than in the reference is determined.
  • Embodiment 21 A method for treating a disease caused or aggravated by STAT3 overexpression in effector cells in a subject suffering therefrom, comprising
  • Embodiment 22 The method of embodiment 21, wherein said method further comprises the steps of
  • step (ii) identifying or having identified a subject profiting from treatment with an iron chelator in case STAT3 hyperactivity and/or overexpression is determined, and wherein step (a) is administering an iron chelator to said subject identified to profit from treatment with an iron chelator.
  • Embodiment 23 A kit comprising an iron chelator or a prodrug thereof and a means of determining STAT3 expression.
  • Embodiment 24 A device comprising (i) an analysis unit comprising a means for determining STAT3 activity and/or expression in a sample, and, operatively connected thereto (ii) an evaluation means comprising tangibly embedded executable instructions for performing a method according to any one of embodiments 18 to 21.
  • Embodiment 25 Else of an iron chelator or prodrug thereof for increasing apoptosis sensitivity in a STAT3 -overexpressing cell, preferably a STAT3 overexpressing cancer cell.
  • Embodiment 26 A combined preparation comprising (i) a pharmaceutically compatible iron chelator or prodrug thereof and (ii) an anticancer agent and/or an immunomodulatory agent for use in treating and/or preventing a disease caused or aggravated by STAT3 overexpression in effector cells in a subject.
  • Embodiment 27 The combined preparation of embodiment 27, wherein said effector cells are HPV-free.
  • Figure 1 Repression of STAT3 protein expression by CPX; immunoblot analysis of STAT3 levels in HPV16-positive SiHa and CaSki cells, as well as in HPV18-positive SW756 and HeLa cervix-carcinoma cells after treatment with 10 mM CPX for the indicated time frames.
  • EtOH solvent control
  • Vinculin loading control.
  • Figure 2 Reduction of phospho(Tyr705)-STAT3 (P-STAT3) levels and of Survivin expression by CPX; immunoblot analysis of SiHa and SW756 cells after treatment with 10 mM CPX for the indicated timeframes; EtOH: solvent control; Vinculin, beta-actin: loading controls.
  • FIG. 3 Repression of STAT3 expression is caused by iron depletion: (a) SiHa (upper panel) and HeLa (lower panel) cells were treated with 100 pM DFO for the indicated timeframes and STAT3 expression was determined by immunoblotting; EtOH: solvent control; beta-actin: load control; (B) SiHa cells were treated with 10 pM CPX for 48 hours, with or without addition of a 3fold molar excess of iron.
  • FAC ferric ammonium citrate
  • FeS0 4 ferric ammonium citrate
  • ZnCh zinc
  • ZnS0 4 zinc
  • 3 ⁇ 40 solvent control
  • ferritin heavy chain (HC) marker for bioavailable iron
  • beta-actin loading control.
  • FIG. 4 CPX treatment and STAT3 transcript levels: SiHa and SW756 cells were treated with 10 pM CPX for the indicated time frames, followed by determining STAT3 mRNA levels via qRT-PCR; mRNA levels are indicated as relative mRNA levels compared to a solvent control (EtOH), which was set to a value of 1.0; similar results were also obtained for CaSki and HeLa cells.
  • EtOH solvent control
  • FIG. 5 Stability measurements on the STAT3 protein: (a) SW756 cells were preincubated for 8 hours with 10 pM CPX or solvent control (EtOH) and treated from time 0 additionally with 10 pg/ml CHX for the indicated timeframes; additionally, a part of the cells was treated additionally with 10 pM MG- 132 or the corresponding solvent control (DMSO); (B) densitometric measurements (normalized to beta-actin) showing a STAT3 halflife in control SW756 cells of approximately 39 hours and in CPX-treated cells of approximately 8.5 hours. A strong reduction of STAT3 expression by CPX was also in all other tumor cells evaluated, including HPV-negative tumor cells.
  • EtOH solvent control
  • DMSO solvent control
  • Figure 6 Canonical and non-canonical STAT3 transcriptional regulation are inhibited by CPX treatment: SiHa and SW756 cells were treated with 10 pM CPX or solvent control for 8, 24 or 48 hours followed by total protein extraction (A) or nuclear-cytoplasmic fractionation (B, C) and analyzation of STAT3 or P-STAT3 levels by immunoblotting. beta-actin was analyzed as loading control. Vinculin was analyzed as cytoplasmic loading and contamination control and lamin A/C as nuclear control.
  • Figure 7 Downregulation of total STAT3 levels in head & neck cancer cells, melanoma cells and colon cancer cells. FaDu head & neck cancer cells, MeWo and SK-Mel28 melanoma cells, and HCT116 colon cancer cells were treated with 10 mM CPX or solvent control (EtOH) for 24 h or 48 h. Total STAT3 protein levels were measured by immunoblot analysis. beta-actin served as loading control..
  • Example 1 iron chelators repress STAT3 protein expression
  • Example 2 CPX induces a destabilisation of the STAT3 protein
  • the STAT3 polypeptide was reported to have a halflife of 24 hours or more (Nie et al. (2015), Drug Des Devel Ther 9:5611). Since STAT3 mRNA levels did not show significant changes upon CPX treatment, it was evaluated whether the treatment destabilizes the STAT3 protein. To this end, HPV-positive cells were treated with CPX and cycloheximide (CHX), a protein biosynthesis inhibitor, and STAT3 protein levels were analyzed over time. It was found that CPX strongly reduces the halflife of the STAT3 protein (Fig. 5). Since this destabilization of STAT3 can be reverted by the protesome inhibitor MG- 132 (Fig. 5), it can be concluded that CPX induces degradation of STAT3 probably via the proteasome pathway.
  • CHX cycloheximide
  • Example 3 Canonical and non-canonical STAT3 transcriptional function are inhibited by CPX
  • P-STAT3 phosphorylated STAT3
  • FIG. 7 depicts examples of STAT3 repression upon CPX treatment in head & neck cancer cells, in melanoma cells, and in colon cancer cells.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un chélateur de fer ou un promédicament pharmaceutiquement compatible de celui-ci destiné à être utilisé dans le traitement et/ou la prévention d'une maladie provoquée ou aggravée par l'hyperactivité de STAT3 dans des cellules effectrices chez un sujet ; et des procédés, des kits, des dispositifs, des utilisations et des préparations combinées
PCT/EP2020/079879 2019-10-25 2020-10-23 Traitement de maladies liées à la stat3 par des chélateurs de fer Ceased WO2021078937A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP19205374.2 2019-10-25
EP19205374 2019-10-25

Publications (1)

Publication Number Publication Date
WO2021078937A1 true WO2021078937A1 (fr) 2021-04-29

Family

ID=68344746

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2020/079879 Ceased WO2021078937A1 (fr) 2019-10-25 2020-10-23 Traitement de maladies liées à la stat3 par des chélateurs de fer

Country Status (1)

Country Link
WO (1) WO2021078937A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016077346A1 (fr) * 2014-11-11 2016-05-19 The University Of Kansas Procédés de traitement du cancer de la vessie avec le ciclopirox, le ciclopirox olamine ou un promédicament à base de ciclopirox
WO2019101897A1 (fr) * 2017-11-23 2019-05-31 Deutsches Krebsforschungszentrum Chélateurs du fer en thérapie antitumorale
WO2019202584A1 (fr) * 2018-04-15 2019-10-24 Mordechai Chevion Compositions et procédés pour le traitement d'une surcharge en fer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016077346A1 (fr) * 2014-11-11 2016-05-19 The University Of Kansas Procédés de traitement du cancer de la vessie avec le ciclopirox, le ciclopirox olamine ou un promédicament à base de ciclopirox
WO2019101897A1 (fr) * 2017-11-23 2019-05-31 Deutsches Krebsforschungszentrum Chélateurs du fer en thérapie antitumorale
WO2019202584A1 (fr) * 2018-04-15 2019-10-24 Mordechai Chevion Compositions et procédés pour le traitement d'une surcharge en fer

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
"Genbank", Database accession no. NP _644805.1
AOKI ET AL., BLOOD, vol. 101, 2003, pages 1535
BRAUN ET AL., INT J CANCER, 2019
CAS , no. 236392-56-6
CAS , no. 30652-11-0
CAS, no. 201530-41-8
CLEMENT ET AL., INT J. CANCER, vol. 100, 2002, pages 491
EBERHARD ET AL., BLOOD, vol. 114, no. 14, 2009, pages 3064
JIABEI WANG ET AL: "The iron chelator Dp44mT inhibits hepatocellular carcinoma metastasis via N-Myc downstream-regulated gene 2 (NDRG2)/gp130/STAT3 pathway", ONCOTARGET, vol. 5, no. 18, 30 September 2014 (2014-09-30), United States, pages 8478 - 8491, XP055764752, ISSN: 1949-2553, DOI: 10.18632/oncotarget.2328 *
NIE ET AL., DRUG DES DEVEL THER, vol. 9, 2015, pages 5611
PEYSER ET AL., CANCER PREV RES, vol. 9, no. 8, 2016, pages 657
SANVISENS ET AL., BIOMED J, vol. 36, no. 2, 2013, pages 51 - 8
SHENHUANG, CURR PHARM DES, vol. 22, 2016, pages 4443
SONG ET AL., CANCER RES., vol. 71, 2011, pages 7628
TORTITORTI, NAT REV CANCER, vol. 13, no. 5, 2013, pages 342
WARISAHSAN, JOURNAL OF CARCINOGENESIS, vol. 5, 2006, pages 14
YANBIN KUANG ET AL: "Iron-dependent CDK1 activity promotes lung carcinogenesis via activation of the GP130/STAT3 signaling pathway", CELL DEATH & DISEASE, vol. 10, no. 4, 1 April 2019 (2019-04-01), XP055764744, DOI: 10.1038/s41419-019-1528-y *
ZHOU ET AL., JOURNAL INTERNATIONAL DU CANCER, vol. 127, no. 10, 2010, pages 2467

Similar Documents

Publication Publication Date Title
US11325892B2 (en) Compounds and methods for treating cancer
Sun et al. Activation of the p62‐Keap1‐NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells
JP2019142880A (ja) 治療薬としてのヒトアンドロゲン受容体ｄｎａ結合ドメイン（ｄｂｄ）化合物およびそれらを使用する方法
EP2359828A1 (fr) Inhibiteurs de HDAC et médicaments ciblant une hormone pour le traitement du cancer
US11312676B2 (en) Small molecule stimulators of steroid receptor coactivator proteins and their use in the treatment of cancer
US20150253330A1 (en) Pre-selection of subjects for therapeutic treatment with an hsp90 inhibitor based on hypoxic status
WO2013056153A1 (fr) Activateurs de pyruvate kinase m2 et méthodes de traitement d&#39;une maladie
US20140113972A1 (en) Preselection of subjects for therapeutic treatment with elesclomol based on hypoxic status
WO2023060227A1 (fr) Inhibiteurs de tead et utilisations associées
US20200009088A1 (en) Compositions and methods for treating androgen-independent cancer
WO2016198698A2 (fr) Inhibiteurs de p38 pour le traitement et la prophylaxie du cancer du foie
US20230039711A1 (en) Ahr inhibitors and uses thereof
WO2021078937A1 (fr) Traitement de maladies liées à la stat3 par des chélateurs de fer
Peng et al. Identification of Bruceine A as a novel HSP90AB1 inhibitor for suppressing hepatocellular carcinoma growth
Chikkegowda et al. Design, synthesis, characterization, and crystal structure studies of Nrf2 modulators for inhibiting cancer cell growth in vitro and in vivo
US20240148757A1 (en) Use of dihydroorotate dehydrogenase (dhodh) inhibitors to target ferroptosis in cancer therapy
US20110275596A1 (en) Methods for treating neoplasia and for identifying compositions useful in such therapy
US20210253628A1 (en) Compounds, compositions, and methods for treatment of androgen-mediated disease
CN109718374B (zh) Irf3抑制剂在制备yap过度激活的癌症的治疗或预防药物中的用途
US20250114313A1 (en) Oligo-benzamide analogs and their use in cancer treatment
Means The Role of UBAP2 in the Pancreas and Pancreatic Disease Etiology
ENDOPLASMIC et al. Bibiana Rius1, Jaleh S. Mesgarzadeh1, Isabelle C. Romine1, Ryan J. Paxman2, Jeffery W. Kelly2, 3, and R. Luke Wiseman1
Chen The Role of Estrogen-Related Receptor Alpha and Heat Shock Protein Family a Member 9 in Thyroid Cancer
WO2025133381A2 (fr) Méthodes de traitement de tumeurs solides
Dixit Interferon-γ modulates intestinal P-glycoprotein: Molecular mechanism and clinical implications

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20797703

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20797703

Country of ref document: EP

Kind code of ref document: A1