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WO2025184594A1 - Modulateurs de la protéolyse de bcl6 et procédés d'utilisation associés - Google Patents

Modulateurs de la protéolyse de bcl6 et procédés d'utilisation associés

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Publication number
WO2025184594A1
WO2025184594A1 PCT/US2025/017973 US2025017973W WO2025184594A1 WO 2025184594 A1 WO2025184594 A1 WO 2025184594A1 US 2025017973 W US2025017973 W US 2025017973W WO 2025184594 A1 WO2025184594 A1 WO 2025184594A1
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WIPO (PCT)
Prior art keywords
compound
lymphoma
cell lymphoma
subject
angioimmunoblastic
Prior art date
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PCT/US2025/017973
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English (en)
Inventor
Dan Sherman
Sheryl Maxine GOUGH
Sarah TANNENBAUM-DVIR
Anna Chiarella VAN ACKER
Sean LANDRETTE
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Arvinas Operations Inc
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Arvinas Operations Inc
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Publication of WO2025184594A1 publication Critical patent/WO2025184594A1/fr
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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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the description provides compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of using those compounds.
  • the compounds are useful as modulators of targeted ubiquitination, such as B-cell lymphoma 6 protein (BCL6), which is degraded by the compounds of the present disclosure.
  • BCL6 B-cell lymphoma 6 protein
  • E3 ubiquitin ligases (of which hundreds are known in humans) confer substrate specificity for ubiquitination, and therefore, are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates.
  • the development of ligands of E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions.
  • recent developments have provided specific ligands which bind to these ligases. For example, since the discovery of nutlins, the first small molecule E3 ligase inhibitors, additional compounds have been reported that target E3 ligases but the field remains underdeveloped.
  • Cereblon is a protein that in humans is encoded by the CRBN gene. CRBN orthologs are highly conserved from plants to humans, which underscores its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates a number of developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb outgrowth in embryos. In the absence of cereblon, DDB1 forms a complex with DDB2 that functions as a DNA damage-binding protein.
  • DDB1 forms a complex with
  • Bifunctional compounds such as those that are described in U.S. Patent Application Publications 2015-0291562 and 2014-0356322 (incorporated herein by reference), function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation.
  • the publications describe bifunctional or proteolysis targeting chimeric (PROTAC) compounds, which find utility as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, which are then degraded and/or otherwise inhibited by the bifunctional compounds.
  • BCL6 B- cell lymphoma 6 protein
  • this application pertains to a method of treating or ameliorating advanced cancer, relapsed/refractory (R/R) cancer, advanced lymphoma, relapsed/refractory (R/R) lymphoma, advanced non-Hodgkin lymphoma (NHL), relapsed/refractory (R/R) nonHodgkin lymphoma (NHL), advanced B-Cell non-Hodgkin lymphoma (NHL), relapsed/refractory (R/R) B-Cell non-Hodgkin lymphoma (NHL), transformed follicular lymphoma, nodal T-follicular helper cell lymphoma (nTEHL), nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTEHL- Al) / advanced angioimmunoblastic T-cell lymphoma (AITL), or relapsed/refractory (R/R) nod
  • this application pertains to a method of treating or ameliorating advanced non-Hodgkin lymphoma (NHL), relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL), transformed follicular lymphoma, nodal T-follicular helper cell lymphoma (nTFHL), relapsed/refractory (R/R) nodal T-follicular helper cell lymphoma, nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL- Al) / advanced angioimmunoblastic T-cell lymphoma (AITL), or relapsed/refractory (R/R) nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL- Al) / angioimmunoblastic T-cell lymphoma (AITL) in a subject in need thereof, comprising
  • the method is for treating advanced non-Hodgkin lymphoma
  • the method is for treating relapsed/refractory (R/R) nonHodgkin lymphoma (NHL).
  • the method is for treating nodal T-follicular helper cell lymphoma (nTFHL).
  • nTFHL nodal T-follicular helper cell lymphoma
  • the method is for treating relapsed/refractory (R/R) nodal T- follicular helper cell lymphoma (nTFHL).
  • R/R relapsed/refractory
  • nTFHL nodal T- follicular helper cell lymphoma
  • the method is for treating nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL-AI) / advanced angioimmunoblastic T-cell lymphoma (AITL).
  • nTFHL-AI nodal T-follicular helper cell lymphoma - angioimmunoblastic type
  • AITL advanced angioimmunoblastic T-cell lymphoma
  • the method is for treating relapsed/refractory (R/R) nodal T- follicular helper cell lymphoma - angioimmunoblastic type (nTFHL-AI) / angioimmunoblastic T-cell lymphoma (AITL).
  • R/R relapsed/refractory nodal T- follicular helper cell lymphoma - angioimmunoblastic type
  • AITL angioimmunoblastic T-cell lymphoma
  • the method is for treating transformed follicular lymphoma.
  • FIG. 1A Exemplary heterobifunctional degradative Compound A comprises a protein targeting moiety (PTM; rectangle), a ubiquitin ligase binding moiety (ULM; triangle), and optionally a linker moiety (L; bold black line) coupling or tethering the PTM to the ULM.
  • FIG. IB Illustration of the functional use of the heterobifunctional degradative Compound A as described herein. Briefly, the ULM recognizes and binds to a specific E3 ubiquitin ligase, and the PTM binds and recruits a target protein bringing it into close proximity to the E3 ubiquitin ligase.
  • the E3 ubiquitin ligase is complexed with an E2 ubiquitin- conjugating protein, and either alone or via the E2 protein catalyzes attachment of ubiquitin small filled ovals) to a lysine on the target protein via an isopeptide bond.
  • the poly- ubiquitinated protein (far right) is then targeted for degradation by the proteasomal machinery of the cell.
  • FIG. 2A Compound A degradation of BCL6 protein in OCI-Lyl cell line. OCI- Lyl was treated with Compound A and its E3-binding deficient analogue for 24-hours.
  • FIG. 2B Compound A degradation of BCL6 protein in germinal center B-cell (GCB) DLBCL cell lines.
  • GCB DLBCL cell lines Farage, SU-DHL-4, SU-DHL-6 and OCI- Ly7
  • FIG. 2C Compound A degradation of BCL6 protein in activated B-cell (ABC) DLBCL cell lines.
  • ABC DLBCL lines SU-DHL-2 and OCLLylO were treated for 24 hours with Compound A.
  • FIG. 3A Antiproliferative effects of Compound A on DLBCL-derived cell lines in 9-day cell growth inhibition assays.
  • GCB lines OCI-Lyl, OCLLy7, SU-DHL-4, and SU-DHL- 6.
  • FIG. 3B Antiproliferative effects of Compound A on DLBCL-derived cell lines in 9-day cell growth inhibition assays.
  • ABC lines SU-DHL-2 and OCLLylO were dosed with a 7-point 3-fold serial dilution of Compound A at a top dose of 30 nM.
  • FIG. 4A Average tumor growth of DLBCL (GCB) cell line derived xenograft model OCI-Lyl with a treatment of Compound A.
  • GCB DLBCL
  • FIG. 4B Average body weights of treated mice.
  • FIG. 5 Tumor lysate BCL6 protein levels in OCI-Lyl cell line xenograft tumor tissue following a treatment time-course with Compound A.
  • FIG. 6 Total Compound A plasma and tumor levels (related to FIG. 5).
  • FIG. 7A Average tumor growth of DLBCL (GCB) cell line derived xenograft model OCI-Lyl with a treatment of Compound A.
  • GCB DLBCL
  • FIG. 7B Average body weights of treated mice.
  • FIG. 7C Tumor lysate BCL6 protein levels 16-hours post-last dose analyzed by western blotting.
  • FIG. 8A Average tumor growth of DLBCL (GCB) cell line derived xenograft model OCLLy7 with a treatment of Compound A.
  • GCB DLBCL
  • FIG. 8B Average body weights of treated mice.
  • FIG. 8C Tumor lysate BCL6 protein levels 16-hours post-last dose analyzed by western blotting.
  • FIG. 9A Average tumor growth of DLBCL (ABC) cell line derived xenograft model SU-DHL-2 with a treatment of Compound A.
  • FIG. 9B Average body weights of treated mice.
  • FIG. 9C Tumor lysate BCL6 protein levels 16-hours post-last dose analyzed by western blotting.
  • FIG. 10A Average tumor growth of DLBCL (ABC) cell line derived xenograft model OCI-LylO with a treatment of Compound A.
  • FIG. 10B Average body weights of treated mice.
  • FIG. 10C Tumor lysate BCL6 protein levels 16-hours post-last dose analyzed by western blotting.
  • FIG. 11A Mean tumor volumes of patient-derived xenograft (PDX) tumors in a mouse model of Double Hit/ diffuse large B-cell lymphoma (DLBCL) treated with Compound A or vehicle as described in Example 10. Data points represent the mean per group and error bars the standard error of the mean.
  • PDX patient-derived xenograft
  • FIG. 11B Mean tumor volumes of patient-derived xenograft (PDX) tumors in a mouse model of unclassified DLBCL treated with Compound A or vehicle as described in Example 10. Data points represent the mean per group and error bars the standard error of the mean.
  • PDX patient-derived xenograft
  • FIG. 11C Mean tumor volumes of patient-derived xenograft (PDX) mouse model of Burkitt’s lymphoma treated with Compound A or vehicle as described in Example 10. Data points represent the mean per group and error bars the standard error of the mean.
  • PDX patient-derived xenograft
  • FIG. 11D Mean tumor volumes of (PDX) mouse model of GCB DLBCL treated with Compound A or vehicle as described in Example 10. Data points represent the mean per group and error bars the standard error of the mean.
  • FIG. 12A Peripheral blood tumor burden of a patient-derived xenograft (PDX) preclinical model of nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL-AI) / angioimmunoblastic T-cell lymphoma (AITL) treated with Compound A, romidepsin or vehicle.
  • PDX patient-derived xenograft
  • nTFHL-AI angioimmunoblastic type
  • AITL angioimmunoblastic T-cell lymphoma
  • FIG. 12B Bone marrow tumor burden in a patient-derived xenograft (PDX) preclinical model of nodal T-follicular helper cell lymphoma angioimmunoblastic type (nTFHL-AI) / angioimmunoblastic T-cell lymphoma (AITL) treated with Compound A, romidepsin or vehicle.
  • PDX patient-derived xenograft
  • nTFHL-AI angioimmunoblastic type
  • AITL angioimmunoblastic T-cell lymphoma
  • FIG. 12C Splenic tumor burden by weight of a patient-derived xenograft (PDX) preclinical model of nodal T-follicular helper cell lymphoma angioimmunoblastic type (nTFHL-AI) / angioimmunoblastic T-cell lymphoma (AITL) treated with Compound A, romidepsin or vehicle.
  • FIG. 13A Mean tumor volumes of a patient-derived xenograft (PDX) model of transformed follicular lymphoma (tFL) treated with Compound A or vehicle.
  • FIG. 13B Mean tumor volumes of a patient-derived xenograft (PDX) model of transformed follicular lymphoma (tFL) treated with Compound A or vehicle.
  • PDX patient-derived xenograft
  • tFL transformed follicular lymphoma
  • a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • ubiquitin ligase refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation.
  • cereblon an E3 ubiquitin ligase protein that alone or in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein, and subsequently targets the specific protein substrates for degradation by the proteasome.
  • E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to targeted proteins.
  • the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth.
  • Polyubiquitination marks proteins for degradation by the proteasome.
  • Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin.
  • different lysines on ubiquitin can be targeted by an E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.
  • patient or “subject” is used throughout the specification to describe an animal, preferably a human or a domesticated animal, to whom treatment, including prophylactic treatment, with the compositions according to the present disclosure is provided.
  • patient refers to that specific animal, including a domesticated animal such as a dog or cat or a farm animal such as a horse, cow, sheep, etc.
  • patient refers to a human patient unless otherwise stated or implied from the context of the use of the term.
  • the term “effective” is used to describe an amount of a compound, composition or component which, when used within the context of its intended use, effects an intended result.
  • the term effective subsumes all other effective amount or effective concentration terms, which are otherwise described or used in the present application.
  • the compound of the disclosure is Compound A:
  • the compound of the disclosure is Compound A: (Compound A).
  • a compound of the disclosure may be synthesized using standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations, including the use of protective groups, as can be obtained from the relevant scientific literature or from standard reference textbooks in the field in view of this disclosure.
  • recognized reference textbooks of organic synthesis include: Smith, M.B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th ed.; John Wiley & Sons: New York, 2001; and Greene, T.W.; Wuts, P.G. M. Protective Groups in Organic Synthesis, 3 rd ; John Wiley & Sons: New York, 1999.
  • Patent Application Publication No. 2022/0395576 and International Publication No. 2022/221673 are incorporated herein by reference in their entireties.
  • the term “independently” is used herein to indicate that the variable, which is independently applied, varies independently from application to application.
  • lymphoma e.g., nonHodgkin lymphoma (NHL) (including, but not limited to, B-Cell non-Hodgkin lymphoma (NHL), transformed follicular lymphoma, nodal T-follicular helper cell lymphoma (nTFHL), and/or nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL- Al) / angioimmunoblastic T-cell lymphoma (AITL)) may refer to a cancer that has spread to one or more areas of the body.
  • NHL nonHodgkin lymphoma
  • NHL nonHodgkin lymphoma
  • nTFHL nodal T-follicular helper cell lymphoma
  • AITL angioimmunoblastic T-cell lymphoma
  • advanced lymphomas e.g., advanced B-Cell non-Hodgkin lymphoma (NHL), transformed follicular lymphoma, nodal T-follicular helper cell lymphoma (nTFHL), and/or advanced nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL- Al) / angioimmunoblastic T-cell lymphoma (AITL)
  • NHLHL- Al angioimmunoblastic type
  • AITL angioimmunoblastic T-cell lymphoma
  • Lugano Classification see, e.g., Hodgkin and Non-Hodgkin Lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 937-58).
  • lymphoma e.g., non- Hodgkin lymphoma (NHL) (including, but not limited to, B-Cell non-Hodgkin lymphoma (NHL), nodal T-follicular helper cell lymphoma (nTFHL), and/or nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL- Al) / angioimmunoblastic T-cell lymphoma (AITL)) may refer to cancer that has reappeared or grown following a period of remission.
  • NHL non- Hodgkin lymphoma
  • NHL non- Hodgkin lymphoma
  • nTFHL nodal T-follicular helper cell lymphoma
  • AITL angioimmunoblastic T-cell lymphoma
  • lymphoma e.g., non- Hodgkin lymphoma (NHL) (including, but not limited to, B-Cell non-Hodgkin lymphoma (NHL), nodal T-follicular helper cell lymphoma (nTFHL), and/or nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL- Al) / angioimmunoblastic T-cell lymphoma (AITL)) may refer to cancer that does not respond to treatment.
  • NHL non- Hodgkin lymphoma
  • NHL B-Cell non-Hodgkin lymphoma
  • nTFHL nodal T-follicular helper cell lymphoma
  • AITL angioimmunoblastic T-cell lymphoma
  • R/R can refer to cancer that is relapsed and/or refractory.
  • “Relapsed/Refractory” or “R/R” can refer to cancer in patients with disease progression who have failed at least one line of therapy.
  • the present disclosure provides a method of treating or ameliorating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject an effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe)-2-aminoethyl
  • Compound A or a pharmaceutically acceptable salt thereof.
  • the compound is Compound A.
  • the present disclosure provides a method of treating or ameliorating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure.
  • the compound (Compound A).
  • the present disclosure provides a method of treating or ameliorating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure.
  • the compound i (Compound A), or a pharmaceutically acceptable salt thereof.
  • treat refers to any action providing a benefit to a patient for which the present compounds may be administered, including the treatment of any disease state or condition which is modulated through the protein to which the present compounds bind.
  • Disease states or conditions, including cancer, which may be treated using compounds according to the present disclosure are set forth hereinabove.
  • the disease or disorder is associated with aberrant BCL6 expression and/or activity.
  • the disease or disorder is a cancer associated with aberrant BCL6 expression and/or activity.
  • the disease or disorder is associated with BCL6 accumulation and aggregation.
  • the disease or disorder is a cancer associated with BCL6 accumulation and aggregation.
  • the disease or disorder is cancer.
  • the cancer is angioimmunoblastic T-cell lymphoma, large B- cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mature B-cell neoplasm, transformed follicular lymphoma, high grade B-cell lymphoma, germinal center B-cell (GCB) DLBCL, activated B-cell (ABC) DLBCL, non-Hodgkin lymphoma not otherwise specified, or solid tumors.
  • GCB germinal center B-cell
  • ABS activated B-cell
  • the cancer is angioimmunoblastic T-cell lymphoma, large B- cell lymphoma, diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma, high grade B-cell lymphoma, germinal center B-cell (GCB) DLBCL, activated B-cell (ABC) DLBCL, and non-Hodgkin lymphoma not otherwise specified, or solid tumors.
  • DLBCL diffuse large B-cell lymphoma
  • follicular lymphoma high grade B-cell lymphoma
  • GCB germinal center B-cell
  • ABSC activated B-cell
  • non-Hodgkin lymphoma not otherwise specified, or solid tumors.
  • the cancer is advanced cancer, relapsed/refractory (R/R) cancer, advanced lymphoma, relapsed/refractory (R/R) lymphoma, advanced non-Hodgkin lymphoma (NHL), relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL), advanced B-Cell nonHodgkin lymphoma (NHL), relapsed/refractory (R/R) B-Cell non-Hodgkin lymphoma (NHL), transformed follicular lymphoma, nodal T-follicular helper cell lymphoma (nTFHL), relapsed/refractory (R/R) nodal T-follicular helper cell lymphoma, nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL- Al) / advanced angioimmunoblastic T-cell lymphoma
  • the cancer is advanced non-Hodgkin lymphoma (NHL), relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL), transformed follicular lymphoma, nodal T-follicular helper cell lymphoma (nTFHL), relapsed/refractory (R/R) nodal T-follicular helper cell lymphoma, advanced nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL-AI) / angioimmunoblastic T-cell lymphoma (AITL), or relapsed/refractory (R/R) nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL-AI) / angioimmunoblastic T-cell lymphoma (AITL).
  • NTL non-Hodgkin lymphoma
  • R/R non-Hodgkin lympho
  • angioimmunoblastic T-cell lymphoma is also known as “AITL”, “Nodal T-follicular helper (TFH) cell lymphoma, angioimmunoblastic-type”, or “nTFHL- AL”.
  • nTFHL nodal T-follicular helper cell lymphoma
  • the cancer is angioimmunoblastic T-cell lymphoma, large B- cell lymphoma, diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma, germinal center B-cell (GCB) DLBCL, activated B-cell (ABC) DLBCL, non-Hodgkin lymphoma not otherwise specified, or solid tumors.
  • DLBCL diffuse large B-cell lymphoma
  • GCB germinal center B-cell
  • ABS activated B-cell
  • non-Hodgkin lymphoma not otherwise specified or solid tumors.
  • the cancer is angioimmunoblastic T-cell lymphoma, large B- cell lymphoma, diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma, high grade B-cell lymphoma, non-Hodgkin lymphoma not otherwise specified, or solid tumors.
  • the cancer is angioimmunoblastic T-cell lymphoma, large B- cell lymphoma, diffuse large B-cell lymphoma (DLBCL), or solid tumors.
  • the cancer is angioimmunoblastic T-cell lymphoma.
  • the cancer is large B-cell lymphoma.
  • the cancer is diffuse large B-cell lymphoma (DLBCL).
  • DLBCL diffuse large B-cell lymphoma
  • the cancer is transformed follicular lymphoma.
  • the cancer is high grade B-cell lymphoma.
  • the cancer is diffuse large B-cell lymphoma (DLBCL), wherein the diffuse large B-cell lymphoma (DLBCL) is selected from germinal center B-cell (GCB) DLBCL and activated B-cell (ABC) DLBCL
  • the cancer is germinal center B-cell (GCB) DLBCL.
  • the cancer is activated B-cell (ABC) DLBCL.
  • the cancer is non-Hodgkin lymphoma not otherwise specified.
  • the cancer is mature B-cell neoplasm.
  • the cancer is solid tumors.
  • the cancer is solid tumors, wherein the solid tumors are selected from breast cancer, lung cancer, ovarian cancer, blastoma, neuroblastoma, and glioblastoma. [00100] In some embodiments, the cancer is breast cancer.
  • the cancer is lung cancer.
  • the cancer is ovarian cancer.
  • the cancer is blastoma.
  • the cancer is neuroblastoma.
  • the cancer is glioblastoma.
  • the cancer is advanced cancer.
  • the cancer is relapsed/refractory (R/R) cancer.
  • the cancer is advanced lymphoma.
  • the cancer is relapsed/refractory (R/R) lymphoma.
  • the cancer is advanced non-Hodgkin lymphoma (NHL).
  • NDL non-Hodgkin lymphoma
  • the cancer is relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL).
  • the cancer is advanced B-Cell non-Hodgkin lymphoma (NHL).
  • the cancer is relapsed/refractory (R/R) B-Cell non-Hodgkin lymphoma (NHL).
  • the cancer is nodal T-follicular helper cell lymphoma (nTFHL). [00115] In some embodiments, the cancer is relapsed/refractory (R/R) nodal T-follicular helper cell lymphoma.
  • the cancer is advanced nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL- Al) / angioimmunoblastic T-cell lymphoma (AITL).
  • nTFHL- Al angioimmunoblastic type
  • AITL angioimmunoblastic T-cell lymphoma
  • the cancer is relapsed/refractory (R/R) nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL-AI) / angioimmunoblastic T-cell lymphoma (AITL).
  • R/R nodal T-follicular helper cell lymphoma - angioimmunoblastic type
  • AITL angioimmunoblastic T-cell lymphoma
  • the cancer is nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL-AI) / angioimmunoblastic T-cell lymphoma (AITL) that has recurred or progressed following institutional standard-of-care therapy.
  • the cancer is transformed follicular lymphoma.
  • neoplasia or “cancer” is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease.
  • malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated.
  • neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors.
  • Exemplary cancers which may be treated by the present compounds either alone or in combination with at least one additional anti-cancer agent include non-Hodgkin lymphoma (NHL) including advanced NHL and relapsed/refractory (R/R) NHL, B-cell non-Hodgkin lymphoma (NHL) including advanced B-cell NHL and relapsed/refractory B-cell (R/R) NHL, transformed follicular lymphoma, nodal T-follicular helper cell lymphoma (nTEHL), relapsed/refractory (R/R) nodal T-follicular helper cell lymphoma, nodal T-follicular helper cell lymphoma (nTEHL), relapsed/refractory (R/R) nodal T-follicular helper cell
  • the present disclosure provides a method of treating or ameliorating diffuse large B-cell lymphoma (DLBCL) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure.
  • DLBCL diffuse large B-cell lymphoma
  • the compound i Compound A
  • the compound is Compound A.
  • Example 1 Compound A degrades BCL6 protein in GCB and ABC DLBCL cell lines.
  • FIG. 2A shows that Compound A treatment demonstrated potent BCL6 protein degradation in OCI-Lyl cell line compared to its E3-binding deficient analogue.
  • FIG. 2B and FIG. 2C showed that Compound A treatment demonstrated potent BCL6 protein degradation in GCB and ABC DLBCL cell lines.
  • Example 2 Compound A inhibits the proliferation of DLBCL cell lines.
  • Example 3 Compound A inhibits the tumor growth of DLBCL (GCB) cell line derived xenograft model OCI-Lyl.
  • GCB DLBCL
  • mice bearing subcutaneous tumors were orally (po) administered vehicle or Compound A at 1, 3, 10, or 30 mg/kg daily for 22 days (qdx22). Dosing began with tumors at an average of 140 mm 3 .
  • FIG. 4A shows average OCI-Lyl tumor growth.
  • FIG. 4B shows average body weights of treated mice.
  • Statistical analyses were performed using 2-way ANOVA: p ⁇ 0.0001 (****). Error bars represent standard error of the mean (+SEM). The data indicate that the treatment with compound A inhibits the tumor growth of DLBCL cell line derived xenograft model OCI-Lyl, the effect was dosing dependent.
  • Example 4 Tumor lysate BCL6 protein levels in OCI-Lyl (GCB) cell line xenograft tumor tissue following a treatment time-course with Compound A.
  • GCB OCI-Lyl
  • Tumor lysate BCL6 protein levels in OCI-Lyl cell line xenograft tumor tissue was measured following a treatment time-course with Compound A.
  • a single dose of Compound A was orally administered in a vehicle of 40% hydroxyprop yl-b-cyclodextrin in pH 3.0 citrate buffer when tumors reached 200-400 mm 3 .
  • Tumors were harvested at the indicated timepoints.
  • Tumor tissue lysates were analyzed using western immunoblotting procedures and densitometry.
  • BCL6 levels are normalized to a GAPDH loading control and presented as a percentage (%) of the average of BCL6 levels in the vehicle control group. Percent BCL6 degradation (%) relative to vehicle is shown above each arm.
  • PIG. 6 showed the total Compound A plasma and tumor levels following a treatment time-course with Compound A. Curves represented average drug levels within each dose group for each tissue type over time. Individual data points were shown to demonstrate spread of the data within each group of seven mice per condition assayed. Compound A achieved maximum concentration (Cmax) at 4-hours in plasma and at 8-hours in tumor tissues. Example 5. Compound A inhibits the tumor growth of DLBCL (GCB) cell line derived xenograft model OCI-Lyl.
  • GCB DLBCL
  • FIG. 7A and FIG. 7B indicate that the treatment with compound A inhibits the tumor growth of DLBCL cell line derived xenograft model OCI-Lyl, the effect was dosing dependent.
  • FIG. 7C depicts tumor lysate BCL6 protein levels 16-hours post-last dose analyzed by western blotting.
  • Example 6 Compound A inhibits the tumor growth of DLBCL (GCB) cell line derived xenograft model OCI-Ly7.
  • GCB DLBCL
  • FIG. 8 A and FIG. 8B indicate that the treatment with compound A inhibits the tumor growth of DLBCL cell line derived xenograft model OCLLy7, the effect was dosing dependent.
  • FIG. 8C depicts tumor lysate BCL6 protein levels 16-hours post-last dose analyzed by western blotting. Individual tumor BCL6 levels are shown in a scatter plot, mean is represented by the bar, determined by densitometry, normalized to GAPDH loading controls, and shown as a percentage of vehicle.
  • Example 7 Compound A inhibits the tumor growth of DLBCL (ABC) cell line derived xenograft model SU-DHL-2.
  • FIG. 9A and FIG. 9B indicate that the treatment with compound A inhibits the tumor growth of DLBCL cell line derived xenograft model SU-DHL-2, the effect was dosing dependent.
  • FIG. 9C depicts tumor lysate BCL6 protein levels 16-hours post-last dose analyzed by western blotting.
  • Example 8 Compound A inhibits the tumor growth of DLBCL(ABC) cell line derived xenograft model OCI-LylO.
  • FIG. 10A and FIG. 10B indicate that the treatment with compound A inhibits the tumor growth of DLBCL cell line derived xenograft model OCI-LylO, the effect was dosing dependent.
  • FIG. 10C depicts tumor lysate BCL6 protein levels 16-hours post-last dose analyzed by western blotting.
  • Example 9 Tumor growth inhibition.
  • Compound A displays 100% TGI in a BCL6 sensitive tumor xenograft model (OCI-Lyl) when dosed at 10 mg/kg (BID).
  • Example 10 Mean tumor volumes of PDX mouse models of DLBCL and Burkitt’s lymphoma, treated with Compound A or vehicle.
  • Compound A orally dosed at 30 mg/kg induces in-vivo tumor regressions in patient derived xenograft (PDX) models of DLBCL and Burkitt’ s lymphoma.
  • PDX patient derived xenograft
  • FIGs. 11A-11D The results are shown in FIGs. 11A-11D.
  • Compound A also induces tumor regressions in models of Burkitt’s lymphoma (LY3148) and GCB DLBCL (LY12962).
  • Example 11 Preclinical model of nodal T-follicular helper cell lymphoma - angioimmunoblastic type (nTFHL-AI) / angioimmunoblastic T-cell lymphoma (AITL) is sensitive to Compound A in vivo
  • Compound A was tested in a systemic cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) -refractory patient derived xenograft (PDX) preclinical model of nTFHL-AI / AITL. After systemic tumor engraftment was confirmed (as determined by flow cytometry quantification of hCD2), Compound A (30 mpk) was administered orally (po), once daily (qd) for 23 days. At the terminal time point (Day 23), tumor burden in peripheral blood, bone marrow and spleen were measured.
  • HDAC histone deacetylase
  • romidespin which is commonly used to treat nTFHL-AI patients
  • FIGs. 12A-12C The percenthCD2+ /hCD45+ cells (FIGs. 12A-12B) or spleen weight (FIG 12C)is reported ⁇ SEM.
  • Compound A significantly decreased tumor cell infiltration in the peripheral blood, bone marrow and spleen as compared to the vehicle control.
  • Tukey’s multiple comparison’s test ** p ⁇ .01, ***p ⁇ 0.001, ****p ⁇ 0.0001.
  • Example 12 Compound A demonstrates efficacy in transformed follicular lymphoma
  • Compound A can be prepared, according to methods known to those skilled in the art, for example, as described in Example 25 of U.S. Patent Application Publication No. 2022/0395576 and International Publication No. 2022/221673, the contents of which are incorporated by reference in their entirety for all purposes.

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Abstract

La présente demande concerne l'utilisation du composé (A) : ou un sel pharmaceutiquement acceptable de celui-ci, pour le traitement de diverses maladies ou troubles, y compris, par exemple, un lymphome non hodgkinien avancé (NHL), un lymphome non hodgkinien récidivant/réfractaire (R/R) (NHL), un lymphome folliculaire transformé, un lymphome nodal à cellules auxiliaires folliculaires T (nTFHL), un lymphome nodal à cellules auxiliaires folliculaires T récidivant/réfractaire (R/R), un lymphome nodal à cellules auxiliaires folliculaires T, type angioimmunoblastique (nTFHL-Al)/un lymphome angioimmunoblastique à cellules T avancé (AITL), ou un lymphome nodal à cellules auxiliaires folliculaires T, type angioimmunoblastique (nTFHL-AI) récidivant/réfractaire (R/R)/lymphome angioimmunoblastique à cellules T (AITL).
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