WO2024137778A1 - Traitements du cancer à l'aide d'inhibiteurs de prmt5 à coopération mta - Google Patents

Traitements du cancer à l'aide d'inhibiteurs de prmt5 à coopération mta Download PDF

Info

Publication number
WO2024137778A1
WO2024137778A1 PCT/US2023/085073 US2023085073W WO2024137778A1 WO 2024137778 A1 WO2024137778 A1 WO 2024137778A1 US 2023085073 W US2023085073 W US 2023085073W WO 2024137778 A1 WO2024137778 A1 WO 2024137778A1
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
cancer
mtap
prmt5
compound
Prior art date
Application number
PCT/US2023/085073
Other languages
English (en)
Inventor
Brian BELMONTES
Paul E. Hughes
Katherine SLEMMONS
Original Assignee
Amgen Inc.
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 Amgen Inc. filed Critical Amgen Inc.
Publication of WO2024137778A1 publication Critical patent/WO2024137778A1/fr

Links

Classifications

    • 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
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases.
  • Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence.
  • epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin.
  • methyltransferases e.g., PRMT5
  • PRMT5 plays a role in diseases such as proliferative disorders, metabolic disorders, and blood disorders.
  • the homozygous deletion of tumor suppressor genes is a key driver of cancer, frequently resulting in the collateral loss of passenger genes located in close genomic proximity to the tumor suppressor. Deletion of these passenger genes can create therapeutically tractable vulnerabilities that are specific to tumor cells.
  • Homozygous deletion of the chromosome 9p21 locus which harbors the well-known tumor suppressor CDKN2A (cyclin dependent kinase inhibitor 2A)
  • CDKN2A cyclin dependent kinase inhibitor 2A
  • MTAP methylthioadenosine phosphorylase
  • Deletion of MTAP results in accumulation of its substrate, methylthioadenosine (MTA).
  • MTA shares close structural similarity to S-adenosylmethionine (SAM), the substrate methyl donor for the type II methyltransferase PRMT5. Elevated MTA levels, driven by loss of MTAP, selectively compete with SAM for binding to PRMT5, placing the methyltransferase in a hypomorphic state, vulnerable to further PRMT5 inhibition.
  • SAM S-adenosylmethionine
  • Multiple genome scale shRNA drop out screens performed in large tumor cell line panels have identified a strong correlation between MTAP loss and cell line dependency on PRMT5, further highlighting the strength of this metabolic vulnerability.
  • PRMT5 is a known cell essential gene and conditional PRMT5 knockout and siRNA knockdown studies suggest that significant liabilities could be associated with inhibiting PRMT5 in normal tissues (e.g.
  • the disclosure provides methods of treating cancer in a patient in need thereof comprising administering to the patient (a) a PRMT5 inhibitor in an amount ranging from 40 mg to 2000 mg, wherein the PRMT5 inhibitor comprises a compound set forth in Formula (I) or having a structure pharmaceutically acceptable salt thereof; wherein
  • X 1 is NH, N(Ci-C 6 alkyl), O, or S;
  • X 2 is N(Ci-C 6 alkyl), O, or S;
  • Y 2 is H, Ci-C 6 alkyl, or Ci-Ce haloalkyl; each of Z 1 and Z 2 is independently H, F, or Ci-Ce alkyl; and each of Z 3 , Z 4 , Z 5 , and Z 6 is independently H, Ci-Cealkyl, or chloride; and
  • a second therapeutic agent selected from a PARP inhibitor, a KRAS inhibitor, or a Kinase-like protein 18A (KIF18A) inhibitor, or a kinase inhibitor.
  • a PARP inhibitor selected from a PARP inhibitor, a KRAS inhibitor, or a Kinase-like protein 18A (KIF18A) inhibitor, or a kinase inhibitor.
  • KIF18A Kinase-like protein 18A
  • Figure 1 is a graph showing that the combination of Compound G and sotorasib resulted in significant anti-tumor activity versus either single agent alone in LU99 NSCLC xenografts.
  • Figure 2 is a graph showing that the combination of Compound B and sotorasib resulted in significant anti-tumor activity versus either single agent alone in LU99 NSCLC xenografts.
  • Figure 3 is a graph showing that the combination of Compound B and sotorasib resulted in significant anti-tumor activity versus either single agent alone in LU5268 NSCLC patient-derived xenografts.
  • Figure 4 is a graph showing that the combination of Compound B and sotorasib resulted in decreased pancreatic cancer (MIAPACA2) cell viability.
  • FIG. 5 is a graph showing that the combination of Compound B and sotorasib significantly reduced pancreatic cancer (MIAPACA2) cell counts.
  • Figure 6A-6C show that the combination of Compound G and sotorasib significantly inhibited tumor growth in MTAP-null, KRAS G12C mutant NSCLC and PDAC xenografts.
  • Figure 6A Mice were implanted with LU99 (NSCLC CDX) tumors
  • Figure 6B LU5268 (NSCLC PDX) tumors.
  • Figure 6C MiaPaCa2 (PDAC CDX) tumors.
  • STATS P values were determined by Linear Mixed-Effects Model with a Tukey's All-Groups comparison: Combination versus either single agent; ****p ⁇ 0.0001.
  • the disclosure provides methods of treating cancer in a patient in need thereof comprising administering to the patient
  • a PRMT5 inhibitor in an amount ranging from 40 mg to 2000 mg, wherein the PRMT5 inhibitor comprises a compound set forth in Formula (I) or having a structure pharmaceutically acceptable salt thereof;
  • X 1 is NH, N(Ci-C 6 alkyl), O, or S;
  • X 2 is N(Ci-C 6 alkyl), O, or S;
  • Y 2 is H, Ci-C 6 alkyl, or Ci-Ce haloalkyl; each of Z 1 and Z 2 is independently H, F, or Ci-Ce alkyl; and each of Z 3 , Z 4 , Z 5 , and Z 6 is independently H, Ci-Cealkyl, or chloride; and
  • the PRMT5 inhibitor has a structure of Formula (S)-l, or a pharmaceutically acceptable salt thereof:
  • X 1 is 0.
  • Z 1 and Z 2 are each H.
  • X 2 is 0.
  • each of Z 3 , Z 4 , Z 5 , and Z 6 is H.
  • Y 2 is Ci-Cehaloalkyl.
  • Y 2 is CF3.
  • the PRMT5 inhibitor is a compound having a structure of:
  • the PRMT5 inhibitor is a compound having a structure of Compound A: salt thereof.
  • the PRMT5 inhibitor is compound having a structure of Compound G: salt thereof.
  • the methods further comprise administering a standard of care therapy to the patient as a combination therapy.
  • a standard of care therapy refers to the administration of two or more therapeutic agents (e.g., a PRMT5 inhibitor as described herein and a second therapeutic agent selected from a PARP inhibitor, a KRAS inhibitor, Kinase-like protein 18A (KIF18A) inhibitor or a kinase inhibitor) to treat cancer.
  • a PRMT5 inhibitor as described herein
  • KIF18A Kinase-like protein 18A
  • such administration encompasses co-administration in multiple, or in separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration.
  • administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times.
  • the second therapeutic agent is a PARP inhibitor.
  • Contemplated PARP inhibitors include, but are not limited to, olaparib, niraparib, rucaparib and talazoparib.
  • the PARP inhibitor is olaparib.
  • Olaparib is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
  • the recommended dose of olaparib for this indication is 400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg.
  • the methods described herein comprise administering 400 mg twice daily to the patient.
  • the second therapeutic agent is a KRAS inhibitor.
  • Contemplated KRAS inhibitors include, but are not limited to, sotorasib (Amgen), adagrasib (MRTX849, Mirati Therapeutics), JDQ443 (Novartis Pharmaceuticals), GDC-6036 (Genentech), D-1553 (InventisBio), LY3537982 (Eli Lilly and Company), Bl 1823911 (Boehringer Ingelheim), JAB-21822 (Jacobio Pharmaceuticals), MK-1084 (Merck), YL-15293 (Shanghai YingLi Pharmaceutical Co.), RMC-6291 (Revolution Medicines), HBI-2438 (HUYABIO International), D3S-001 (D3 Bio (Wuxi) Co.), APG-1842 (Ascentage Pharma), VRTX126 (VRise Therapeutics), AZD4625 (AstraZeneca), ASP2453 (Astellas Pharma), ERAS-34
  • the KRAS inhibitor is sotorasib.
  • Sotorasib is a small molecule that irreversibly inhibits the KRAS G12C mutant protein. Sotorasib is also referred to as AMG 510 or 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4- [(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1 -yl]pyrido[2,3-d]pyrimidin-2(1 H)-one and has the following structure:
  • Dosage information can be found in LUMAKRAS® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revision 11/2022), which is herein incorporated by reference in its entirety.
  • the methods disclosed herein comprise administering 960 mg sotorasib once daily to the patient.
  • the methods disclosed herein comprise administering 240 mg sotorasib once daily to the patient.
  • the second therapeutic agent is a KIF18A inhibitor.
  • KIF18A inhibitor means any compound useful for modulating KIF18A protein alone or in a bound complex with microtubules (MT) for treating KIF18A-mediated conditions and/or diseases, e.g., cancer.
  • the KIF18A inhibitor is N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide and has the following structure:
  • the second therapeutic agent is a kinase inhibitor.
  • Contemplated kinase inhibitors include, but are not limited to, pablociclib, trametinib. bosutinib, crizotinib, dasatinib, erlotinib, osimertinib, gefitinib, lapatinib, pazopanib, ruxolitinib, sunitinib, and vemurafenib.
  • the kinase inhibitor is pablociclib.
  • the kinase inhibitor is trametinib.
  • a “therapeutically effective amount” of a PRMT5 inhibitor means an amount effective to treat or to prevent development of, or to alleviate the existing symptoms of, the patient being treated. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, a “therapeutically effective dose” refers to that amount of a PRMT5 inhibitor described herein that results in achieving the desired effect.
  • a therapeutically effective amount of a PRMT5 inhibitor described herein decreases MTAP activity by at least 5%, compared to control, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%.
  • a PRMT5 inhibitor described herein is administered to a patient in need thereof orally and once a day.
  • a "patient” or “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult.
  • a pediatric subject e.g., infant, child, adolescent
  • adult subject e.g., young adult, middle-aged adult or senior adult.
  • human human
  • patient and “subject” are used interchangeably herein.
  • the methods comprise administering a PRMT5 inhibitor described herein in an amount ranging from 40 mg to 2000 mg.
  • the PRMT5 inhibitor is administered in a divided daily dose, such as two, three, four, five, or six times a day.
  • the methods comprises administering 40 mg, 120 mg, 240 mg, 480 mg, 960 mg, 1600 mg, or 2000 mg of the PRMT5 inhibitor to the patient once daily.
  • the cancer is a MTAP -deleted cancer.
  • a MTAP-deleted (or "MTAP-null”) cancer refers to a cancer that lacks expression of the enzyme methylthioadenosine phosphorylase (MTAP).
  • the MTAP gene located at chromosomal locus 9p21 is frequently co-deleted with the CDKN2A and CDKN2B genes.
  • Selective MTAP deficiency refers to deficiency without co-deletion of the CDKN2 genes, due either to selective deletion of the MTAP locus or to methylation of the MTAP promoter.
  • MTAP-null cancers include MTAP-deficiency in at least 1% of disease cells. Terms "MTAP-null” and “MTAP-deleted” are used interchangeably herein.
  • the cancer is an MTAP-deficient and/or MTA-accumulating cancer.
  • An "MTAP- deficiency-related” or “MTAP-deficiency” or “MTAP deficient” disease for example, a proliferating disease, e.g., a cancer) or a disease (for example, a proliferating disease, e.g., a cancer)"associated with MTAP deficiency” or a disease (for example, a proliferating disease, e.g., a cancer) "characterized by MTAP deficiency” and the like refer to an ailment (for example, a proliferating disease, e.g., a cancer) wherein a significant number of cells are MTAP-deficient.
  • one or more disease cells can have a significantly reduced post-translational modification, production, expression, level, stability and/or activity of MTAP.
  • MTAP -deficiency-related diseases include, but are not limited to, cancers, including but not limited to: glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sar
  • some disease cells e.g., cancer cells
  • some disease cells may be MTA-accumulating while others are not.
  • the present disclosure encompasses methods of treatment involving diseases of these tissues, or any other tissues, wherein the proliferation of MTAP-deficient and/or MTA- accumulating cells can be inhibited by administration of a PRMT5 inhibitor.
  • Some cancer cells which are MTAP-deficient are also deficient in CDKN2A; the post- translational modification, production, expression, level, stability and/or activity of the CDKN2A gene or its product are decreased in these cells.
  • MTAP and CDKN2A are in close proximity on chromosome 9p21; MTAP is located approximately 100 kb telomeric to CDKN2A. Many cancer cell types harbor CDKN2A/MTAP loss (loss of both genes). Thus, in some embodiments, a MTAP-deficient cell is also deficient in CDKN2A.
  • the patient has a cancer further comprising a KRAS G12C mutation.
  • KRAS G12C mutations occur with the alteration frequencies shown in the table below (Gerami et al., Cancer Discov. 2012, 2(5), 401; Gao et al., Science Signaling 2013, 6(269), pH ).
  • the table shows that 11.6% of patients with non-small cell lung cancer have a cancer, wherein one or more cells express KRAS G12C protein.
  • the cancer is cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers (e.g. Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, triple negative breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extra
  • the cancer is glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary
  • the MTAP-null cancer is lung cancer, biliary tract cancer, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, gallbladder cancer, or mesothelioma.
  • the cancer is a solid tumor. In some embodiments, the tumor is malignant.
  • Exemplary MTAP-null solid tumors include, but are not limited to, MTAP-null brain cancer (including, but not limited to, MTAP-null glioma, MTAP-null oligodendroglioma, MTAP-null glioblastoma multiforme, MTAP- null astrocytoma, MTAP-null medulloblastoma, MTAP-null ependymoma, and MTAP-null meningioma), MTAP- null head and neck cancer (including, but not limited to, MTAP-null salivary gland (parotid) tumors, MTAP-null head and neck squamous cell carcinoma, and MTAP-null thyroid cancer), MTAP-null breast cancer (including, but not limited to, invasive ductal breast cancer, mixed mucinous breast cancer and lobular carcinoma),
  • the MTAP-null cancer is a hematologic tumor.
  • hematologic tumors include, but are not limited to, MTAP-null leukemia (including, but not limited to, MTAP-null acute lymphocytic leukemia, MTAP-null acute myeloid leukemia), MTAP-null lymphoma (including, but not limited to, MTAP-null mantle cell lymphoma, MTAP-null follicular lymphoma, MTAP-null diffuse large B cell lymphoma, and MTAP-null mycosis fungoides).
  • MTAP-null leukemia including, but not limited to, MTAP-null acute lymphocytic leukemia, MTAP-null acute myeloid leukemia
  • MTAP-null lymphoma including, but not limited to, MTAP-null mantle cell lymphoma,
  • compositions containing a PRMT5 inhibitor described herein can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. [0040] Monitoring Efficacy of T reatment
  • the efficacy of a given treatment for cancer can be determined by the skilled clinician. However, a treatment is considered "effective treatment," as the term is used herein, if any one or all of the signs or symptoms of e.g., a tumor are altered in a beneficial manner or other clinically accepted symptoms are improved, or even ameliorated, e.g., by at least 10% following treatment with an agent as described herein. Efficacy can also be measured by a failure of an individual to worsen as assessed by hospitalization or need for medical interventions (i.e., progression of the disease is halted). Methods of measuring these indicators are known to those of skill in the art and/or described herein.
  • the combination therapy described herein exhibits a combination benefit.
  • the term "combination benefit” refers to an observed efficacy with a combination therapy that is higher than treatment with either individual therapy alone.
  • the combination therapy described herein exhibits a combination benefit compared to PRMT5 monotherapy.
  • the combination therapy described herein exhibits a combination benefit compared to monotherapy with a second therapeutic described herein.
  • a method of treating cancer in a patient in need thereof comprising administering to the patient (a) a PRMT5 inhibitor in an amount ranging from 40 mg to 2000 mg, wherein the PRMT5 inhibitor comprises a compound set forth in ⁇ Formula 1 > or having a structure pharmaceutically acceptable salt thereof; wherein
  • X 1 is NH, N(Ci-C 6 alkyl), O, or S;
  • X 2 is N(Ci-C 6 alkyl), O, or S;
  • Y 2 is H, Ci-C 6 alkyl, or Ci-Ce haloalkyl; each of Z 1 and Z 2 is independently H, F, or Ci-Ce alkyl; and each of Z 3 , Z 4 , Z 5 , and Z 6 is independently H, Ci-Cealkyl, or chloride; and (b) a second therapeutic agent selected from a PARP inhibitor, a KRAS inhibitor, a Kinase-like protein 18A (KIF18A) inhibitor, or a kinase inhibitor.
  • a second therapeutic agent selected from a PARP inhibitor, a KRAS inhibitor, a Kinase-like protein 18A (KIF18A) inhibitor, or a kinase inhibitor.
  • KRAS inhibitor is sotorasib, adagrasib, JNJ- 74699157, LY3537982, Bl 1823911, Bl 1701963, GDC-6036, tetrahydroquinazoline, JAB-2122, ARS-3248, AZD4625, or MRTX1133.
  • Table 1 Representative Compound B and olaparib concentrations and corresponding combination Fa and Cl scores in SUM149PT cells.
  • Table 2 Representative Compound B and olaparib concentrations and corresponding combination Fa and Cl scores in HCC1395 cells.
  • Table 3 Representative Compound G and olaparib concentrations and corresponding combination Fa and Cl scores in HCC1395 cells.
  • Pancreatic cancer cell lines (MIAPACA2T2) were treated with the combination of PRMT5 inhibitor (i.e., Compound B or Compound G) and sotorasib for 6 days.
  • PRMT5 inhibitor e.g., Compound B or Compound G
  • PRMT5 inhibitor was performed at a 1.9-fold dilution series and the combination partner was performed at 1.2 to 1.7 fold dilution series to create an 8 x 10 dose matrix including DMSO-only controls.
  • Cell viability was measured by the CellTiter-Glo Luminescence assay. Raw luminescent values were converted to fraction affected (Fa) with the following equation:
  • Table 4 Representative Compound B and sotorasib concentrations and corresponding combination Fa and Cl scores in MIAPACA2T2 cells.
  • Table 5 Representative Compound G and sotorasib concentrations and corresponding combination Fa and Cl scores in MIAPACA2T2 cells.
  • Bladder cancer cell lines (UM-UC-3) were treated with the combination of PRMT5 inhibitor (i ,e. , Compound B) and sotorasib for 6 days.
  • PRMT5 inhibitor e.g., Compound B
  • PRMT5 inhibitor was performed at a 1.9-fold dilution series and the combination partner was performed at 1 .2 to 1 .7 fold dilution series to create an 8 x 10 dose matrix including DMSO-only controls.
  • Cell viability was measured by the CellTiter-Glo Luminescence assay.
  • Lung cancer cell lines were treated with the combination of PRMT5 inhibitor (i.e., Compound B or Compound G) and sotorasib for 6 days.
  • PRMT5 inhibitor i.e., Compound B or Compound G
  • the combination partner was performed at 1.2 to 1.7 fold dilution series to create an 8 x 10 dose matrix including DMSO-only controls.
  • Cell viability was measured by the CellTiter-Glo Luminescence assay. Raw luminescent values were converted to fraction affected (Fa) with the following equation:
  • Table 7 Representative Compound B and sotorasib concentrations and corresponding combination Fa and Cl scores in LU99 cells.
  • Table 8 Representative Compound G and sotorasib concentrations and corresponding combination Fa and Cl scores in LU99 cells.
  • Pancreatic cancer cell lines (PSN1 and MIAPACA2T2) were treated with the combination of PRMT5 inhibitor (i.e., Compound B or Compound G) and KIF18A for 6 days.
  • PRMT5 inhibitor e.g., Compound B or Compound G
  • PRMT5 inhibitor was performed at a 1.9-fold dilution series and the combination partner was performed at 1.2 to 1 .7 fold dilution series to create an 8 x 10 dose matrix including DMSO-only controls.
  • Cell viability was measured by the CellTiter-Glo Luminescence assay. Raw luminescent values were converted to fraction affected (Fa) with the following equation:
  • Table 9 Representative Compound B and KIF18A concentrations and corresponding combination Fa and Cl scores in PSN1 cells.
  • Table 10 Representative Compound G and KIF18A concentrations and corresponding combination Fa and Cl scores in PSN1 cells.
  • Table 11 Representative Compound B and KI F18A concentrations and corresponding combination Fa and Cl scores in MIAPACA2T2 cells.
  • Lung cancer cell lines were treated with the combination of PRMT5 inhibitor (e.g., Compound B) and KIF18A for 6 days.
  • PRMT5 inhibitor i.e., Compound B
  • PRMT5 inhibitor was performed at a 1.9-fold dilution series and the combination partner was performed at 1 .2 to 1 .7 fold dilution series to create an 8 x 10 dose matrix including DMSO-only controls.
  • Cell viability was measured by the CellTiter-Glo Luminescence assay. Raw luminescent values were converted to fraction affected (Fa) with the following equation:
  • Table 13 Representative Compound B and KIF18A concentrations and corresponding combination Fa and Cl scores in LU99 cells.
  • Lung cancer cell lines were treated with the combination of PRMT5 inhibitor (e.g., Compound B and Compound G) and KRAS G12X inhibitor for 6 days.
  • PRMT5 inhibitor e.g., Compound B or Compound G
  • PRMT5 inhibitor was performed at a 1.9-fold dilution series and the combination partner was performed at 1.2 to 1.7 fold dilution series to create an 8 x 10 dose matrix including DMSO-only controls.
  • Cell viability was measured by the Cel ITiter-Glo Luminescence assay. Raw luminescent values were converted to fraction affected (Fa) with the following equation:
  • Table 14 Representative Compound B and KRAS G12X inhibitor concentrations and corresponding combination Fa and Cl scores in A549 cells.
  • Table 15 Representative Compound G and KRAS G12X inhibitor concentrations and corresponding combination Fa and Cl scores in A549 cells.
  • Lung cancer cell lines H292 and A549 were treated with the combination of PRMT5 inhibitor (e.g., Compound B and Compound G) and palbociclib for 6 days.
  • PRMT5 inhibitor e.g., Compound B or Compound G
  • PRMT5 inhibitor was performed at a 1 .9-fold dilution series and the combination partner was performed at 1 .2 to 1 .7 fold dilution series to create an 8 x 10 dose matrix including DMSO-only controls.
  • Cell viability was measured by the Cel ITiter-Glo Luminescence assay. Raw luminescent values were converted to fraction affected (Fa) with the following equation:
  • Table 16 Representative Compound B and palbociclib concentrations and corresponding combination Fa and Cl scores in H292 cells. [0079] Table 17. Representative Compound G and palbociclib concentrations and corresponding combination Fa and Cl scores in H292 cells.
  • Table 18 Representative Compound B and palbociclib concentrations and corresponding combination Fa and Cl scores in A549 cells.
  • Table 19 Representative Compound G and palbociclib concentrations and corresponding combination Fa and Cl scores in A549 cells.
  • Lung cancer cell lines were treated with the combination of PRMT5 inhibitor (e.g., Compound B and Compound G) and trametinib for 6 days.
  • PRMT5 inhibitor e.g., Compound B or Compound G
  • PRMT5 inhibitor was performed at a 1.9-fold dilution series and the combination partner was performed at 1.2 to 1.7 fold dilution series to create an 8 x 10 dose matrix including DMSO-only controls.
  • Cell viability was measured by the CellTiter-Glo Luminescence assay. Raw luminescent values were converted to fraction affected (Fa) with the following equation:
  • Table 20 Representative Compound G and trametinib concentrations and corresponding combination Fa and Cl scores in A549 cells.
  • Table 21 Representative Compound G and trametinib concentrations and corresponding combination Fa and Cl scores in A549 cells.
  • Pancreatic cancer cell lines (MIAPACA2T2) were treated with the combination of PRMT5 inhibitor (i.e., Compound B and Compound G) and trametinib for 6 days.
  • PRMT5 inhibitor e.g., Compound B or Compound G
  • PRMT5 inhibitor was performed at a 1.9-fold dilution series and the combination partner was performed at 1.2 to 1.7 fold dilution series to create an 8 x 10 dose matrix including DMSO-only controls.
  • Cell viability was measured by the Cel ITiter-Glo Luminescence assay. Raw luminescent values were converted to fraction affected (Fa) with the following equation:
  • Table 23 Representative Compound G and trametinib concentrations and corresponding combination Fa and Cl scores in MIAPACA2T2 cells.
  • Example 11 Combination of PRMT5 inhibitor and sotorasib inhibited tumor growth in LU99 NSCLC Xenografts
  • Example 14 Combination of PRMT5 inhibitor and sotorasib inhibited cell viability in a pancreatic cancer cell line
  • Pancreatic cancer cell line (MIAPACA2) was treated with the combination of PRMT5 inhibitor (e.g., Compound B) and sotorasib for 6 days.
  • PRMT5 inhibitor e.g., Compound B
  • the combination partner was performed at 2- fold dilution series to create an 6 x 10 dose matrix including DMSO-only controls.
  • Cell viability was measured by the CellTiter-Glo Luminescence assay after 6 days.
  • the combination of Compound B and sotorasib resulted in reduced MIAPACA2 cell viability.
  • nuclear counts were performed on the IncuCyte live cell imager over 8 days.
  • MIAPACA2 cells were treated with DMSO, 150nM Compound B, 50nM sotorasib, or combination (150nM Compound B + 50nM sotorasib). Results are shown in Figure 5.
  • Pancreatic cancer cell line (MIAPACA2) was treated with the combination of PRMT5 inhibitor (i.e., PRMT5 inhibitor).
  • PRMT5 inhibitor i.e., Compound B
  • the combination partner was performed at 1 .2 to 1 .7 fold dilution series to create an 8 x 10 dose matrix including DMSO-only controls.
  • Cell viability was measured by the CellTiter-Glo Luminescence assay. Raw luminescent values were converted to fraction affected (Fa) with the following equation:
  • Table 24 Representative Compound B and sotorasib concentrations and corresponding Cl scores in MIAPACA2 cells.
  • a MTAP-null NSCLC cancer cell line (H1650) was treated with the combination of Compound G and osimertinib for 6 days.
  • Compound G was performed at a 1 .9-fold dilution series and the combination partner was performed at 1.2 to 1.7 fold dilution series to create an 8 x 10 dose matrix including DMSO-only controls.
  • Cell viability was measured by the Cel ITi ter-Glo Luminescence assay. Raw luminescent values were converted to fraction affected (Fa) with the following equation:
  • Synergy analysis was performed using the CalcuSyn software to determine Cl scores based on the drug concentrations used and corresponding Fa values. Results are shown in Tables 25. *CI Values (Calcusyn): Strong Synergism: 0.1 -0.3; Synergism: 0.3-0.7; Moderate Synergism: 0.7-0.85; Slight Synergism: 0.85-0.9;
  • Table 25 Representative Compound G and osimertinib concentrations and corresponding combination Fa and Cl scores in H1650 cells.
  • a MTAP-null NSCLC cancer cell line (H1650) was treated with the combination of Compound G and erlotinib for 6 days.
  • Compound G was performed at a 1 .9-fold dilution series and the combination partner was performed at 1 .2 to 1 .7 fold dilution series to create an 8 x 10 dose matrix including DMSO-only controls.
  • Cell viability was measured by the Cel ITi ter-Glo Luminescence assay. Raw luminescent values were converted to fraction affected (Fa) with the following equation:
  • Table 26 Representative Compound G and erlotinib concentrations and corresponding combination Fa and Cl scores in H1650 cells.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes de traitement du cancer chez un patient comprenant l'administration d'un inhibiteur de PRMT5 et d'un inhibiteur de PARP, d'un inhibiteur de KRAS ou d'un inhibiteur de protéine de type kinase 18A (KIF18A) ou d'un inhibiteur de kinase au patient.
PCT/US2023/085073 2022-12-21 2023-12-20 Traitements du cancer à l'aide d'inhibiteurs de prmt5 à coopération mta WO2024137778A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202263434268P 2022-12-21 2022-12-21
US63/434,268 2022-12-21
US202363459315P 2023-04-14 2023-04-14
US63/459,315 2023-04-14
US202363543613P 2023-10-11 2023-10-11
US63/543,613 2023-10-11

Publications (1)

Publication Number Publication Date
WO2024137778A1 true WO2024137778A1 (fr) 2024-06-27

Family

ID=89771740

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/085073 WO2024137778A1 (fr) 2022-12-21 2023-12-20 Traitements du cancer à l'aide d'inhibiteurs de prmt5 à coopération mta

Country Status (1)

Country Link
WO (1) WO2024137778A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021163344A1 (fr) * 2020-02-12 2021-08-19 Amgen Inc. Nouveaux inhibiteurs de prmt5
WO2022216648A1 (fr) * 2021-04-08 2022-10-13 Mirati Therapeutics, Inc. Polythérapies faisant appel à des inhibiteurs de prmt5 pour le traitement du cancer
US20220395508A1 (en) * 2019-10-22 2022-12-15 Lupin Limited Pharmaceutical combination of prmt5 inhibitors
WO2023034786A1 (fr) * 2021-08-30 2023-03-09 Amgen Inc. Procédé de synthèse de dérivés de naphtyridine et d'intermédiaires de ceux-ci
WO2023196545A1 (fr) * 2022-04-08 2023-10-12 Amgen Inc. Traitements du cancer à l'aide d'inhibiteurs de prmt5 à coopération mta

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220395508A1 (en) * 2019-10-22 2022-12-15 Lupin Limited Pharmaceutical combination of prmt5 inhibitors
WO2021163344A1 (fr) * 2020-02-12 2021-08-19 Amgen Inc. Nouveaux inhibiteurs de prmt5
WO2022216648A1 (fr) * 2021-04-08 2022-10-13 Mirati Therapeutics, Inc. Polythérapies faisant appel à des inhibiteurs de prmt5 pour le traitement du cancer
WO2023034786A1 (fr) * 2021-08-30 2023-03-09 Amgen Inc. Procédé de synthèse de dérivés de naphtyridine et d'intermédiaires de ceux-ci
WO2023196545A1 (fr) * 2022-04-08 2023-10-12 Amgen Inc. Traitements du cancer à l'aide d'inhibiteurs de prmt5 à coopération mta

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CERAMI ET AL., CANCER DISCOV., vol. 2, no. 5, 2012, pages 401
GAO ET AL., SCIENCE SIGNALING, vol. 6, 2013, pages 269

Similar Documents

Publication Publication Date Title
US20210100813A1 (en) Combination therapy for cancer using bromodomain and extra-terminal (bet) protein inhibitors
RU2508110C2 (ru) КОМБИНАЦИЯ (А) ИНГИБИТОРА ФОСФОИНОЗИТ-3-КИНАЗЫ И (Б) МОДУЛЯТОРА ПУТИ Ras/Raf/Mek
RU2747788C2 (ru) Комбинированная терапия ингибиторами notch и cdk4/6 для лечения рака
US20040106605A1 (en) Synergistic methods and compositions for treating cancer
EP2786754B1 (fr) Thérapie de combinaison avec un inhibiteur de la mitose
RU2496500C2 (ru) Применение производных пиримидина для лечения egfr-зависимых заболеваний или заболеваний с приобретенной резистентностью к агентам, направленным против членов семейства egfr
US11369585B2 (en) Compositions, methods, systems and/or kits for preventing and/or treating neoplasms
Reardon et al. Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma
BR112019016737A2 (pt) Terapia anticâncer combinada
Chen et al. Novel PI3K/Akt/mTOR pathway inhibitors plus radiotherapy: strategy for non-small cell lung cancer with mutant RAS gene
WO2023196545A1 (fr) Traitements du cancer à l'aide d'inhibiteurs de prmt5 à coopération mta
EP2981169B1 (fr) Méthodes et compositions pour traiter les cancers ayant acquis une résistance aux médicaments chimiothérapiques et ciblés faisant appel à l'orotate de carboxyamidotriazole
EP2968564B1 (fr) Combinaisons d'inhibiteurs de mek, d'egfr et d'erbb2 dans le traitement du cancer du poumon à kras mutant
KR20230057384A (ko) 조합 요법
WO2018092064A1 (fr) Combinaisons d'inhibiteurs de mdm2 et d'inhibiteurs de bcl-xl
WO2024137778A1 (fr) Traitements du cancer à l'aide d'inhibiteurs de prmt5 à coopération mta
KR20240021237A (ko) 두경부암 치료를 위한 egfr 저해제
CN102105148B (zh) 包含aurora激酶抑制剂和抗肿瘤药的治疗组合
WO2024118897A1 (fr) Traitements du cancer utilisant un inhibiteur de prmt5 et un inhibiteur de mat2a
CN102105147B (zh) 包含aurora激酶抑制剂和抗肿瘤药的治疗组合
Moore et al. Defactinib hydrochloride. Dual FAK1/PYK2 inhibitor, Treatment of non-small cell lung cancer, treatment of malignant mesothelioma, treatment of ovarian cancer
WO2023168491A1 (fr) Traitement de l'adénocarcinome du rein à cellules claires
CA3241001A1 (fr) Methodes et schemas posologiques comprenant un inhibiteur de cdk2 et un inhibiteur de cdk4 pour le traitement du cancer
CA3168936A1 (fr) Combinaison comprenant de l'alpelisib et de l'acide 6-(2,4-dichlorophenyle)-5-[4-[(3s)-1-(3-fluoropropyl) pyrrolidin-3-yl] oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylique
NZ786604A (en) Combination therapy with notch and cdk4/6 inhibitors for the treatment of