CN118043053A - Methods of treating cancer - Google Patents
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- CN118043053A CN118043053A CN202280064545.1A CN202280064545A CN118043053A CN 118043053 A CN118043053 A CN 118043053A CN 202280064545 A CN202280064545 A CN 202280064545A CN 118043053 A CN118043053 A CN 118043053A
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Abstract
The present disclosure features useful methods of treating cancer, e.g., in a subject in need thereof. In some embodiments, the methods comprise administering an agent that reduces the level and/or activity of BRM/BRG1 in combination with immunotherapy. In some embodiments, the immunotherapy is administered concurrently with an agent that reduces the level and/or activity of BRM and/or BRG1 in the subject. In some embodiments, the immunotherapy is administered prior to an agent that reduces the level and/or activity of BRM and/or BRG1 in the subject. In some embodiments, the immunotherapy is administered after an agent that reduces the level and/or activity of BRM and/or BRG1 in the subject.
Description
Cross Reference to Related Applications
The present application claims the benefit of U.S. provisional application No. 63/227,111 filed on 7.29 of 2021 and U.S. provisional application No. 63/280,430 filed on 11.17 of 2021. The contents of the foregoing application are incorporated by reference herein in their entirety.
Background
The present invention relates to methods of treating cancer with compounds that modulate BRG1 or BRM-associated factor (BAF) complexes.
Chromatin regulation is critical for gene expression, and ATP-dependent chromatin remodeling is the mechanism by which such gene expression occurs. Human switch/sucrose non-fermentation (SWI/SNF) chromatin remodeling complexes (also known as BAF complexes) have two SWI 2-like atpases, known as BRG1 (Brahma-related gene 1) and BRM (Brahma). The transcriptional activator BRG1, also known as the ATP-dependent chromatin remodeling factor SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in some cancer tumors and is required for proliferation of cancer cells. BRM, also known as the possible global transcriptional activator SNF2L2 and/or ATP-dependent chromatin remodeling factor SMARCA2, is encoded by the SMARCA2 gene on chromosome 9 and has been shown to be critical for tumor cell growth of cells characterized by BRG1 loss-of-function mutations. Inactivation of BRG and/or BRM results in downstream effects on cells, including cell cycle arrest and tumor suppression.
Immunotherapy using the immune system of a patient has been found to be effective in treating many different cancer types and has become an important part of cancer therapy. However, some cancers respond poorly to immunotherapy. Therefore, there is a need to develop methods to increase the responsiveness of cancer to immunotherapy.
Disclosure of Invention
The invention features a useful method of treating cancer, for example, in a subject in need thereof. In some embodiments, the methods described herein comprise administering a BRM and/or BRG-1 inhibitor in combination with an immunotherapy for the treatment of cancer.
In one aspect, the invention features a method of treating cancer in a subject in need thereof. The method comprises the step of administering to the subject (i) an effective amount of an agent that decreases BRM and/or BRG1 levels and/or activity in the subject and (ii) an effective amount of immunotherapy.
In some embodiments, the immunotherapy is administered concurrently with an agent that decreases BRM and/or BRG1 levels and/or activity in the subject. In some embodiments, the immunotherapy is administered prior to (e.g., at least one hour prior, at least twelve hours prior, at least one day prior, at least one week prior, at least two weeks prior, at least four weeks prior) the agent that reduces BRM and/or BRG1 levels and/or activity in the subject. In some embodiments, the immunotherapy is administered after (e.g., at least one hour after, at least twelve hours after, at least one day after, at least one week after, at least two weeks after, at least four weeks after) an agent that reduces BRM and/or BRG1 levels and/or activity in the subject.
In some embodiments, the cancer fails to respond to a previously administered immunotherapy. In some embodiments, the cancer is resistant to immunotherapy (e.g., tolerance is determined or predicted).
In one embodiment of any of the foregoing methods, the immunotherapy is CTLA-4 inhibitor, PD-1 inhibitor, PD-L1 inhibitor, or adoptive T cell transfer therapy. In some embodiments, the immunotherapy is a PD-1 inhibitor (such as a PD-1 antibody), a PD-L1 inhibitor (such as a PD-L1 antibody), a CTLA-4 inhibitor (such as a CTLA-4 antibody or fusion protein), a CSF-1R inhibitor, IDO inhibitor, an A1 adenosine inhibitor, an A2A adenosine inhibitor, an A2B adenosine inhibitor, an A3A adenosine inhibitor, an arginase inhibitor, or an HDAC inhibitor. In some embodiments, the immunotherapy is a PD-1 inhibitor (e.g., nal Wu Shankang, palbociclib, pilizumab, or BMS 936559). In some embodiments, the immunotherapy is a PD-L1 inhibitor (e.g., atilizumab or MEDI 4736). In some embodiments, the immunotherapy is a CTLA-4 inhibitor (e.g., ipilimumab). In some embodiments, the immunotherapy is a CSF-1R inhibitor (e.g., pexidasatinib or AZD 6495). In some embodiments, the immunotherapy is an IDO inhibitor (e.g., norhalman, rosmarinic acid, or α -methyl-tryptophan). In some embodiments, the immunotherapy is an A1 adenosine inhibitor (e.g., 8-cyclopentyl-1, 3-dimethylxanthine, 8-cyclopentyl-1, 3-dipropylxanthine, 8-phenyl-1, 3-dipropylxanthine, pamidronate, BG-9719, BG-9928, FK-453, FK-838, luo Ge theophylline (rolofylline), or N-0861). In some embodiments, the immunotherapy is an A2A adenosine inhibitor (e.g., ATL-4444, itratheophylline, MSX-3, readnan (preladenant), SCH-58261, SCH-412,348, SCH-442,416, ST-1535, VER-6623, VER-6947, VER-7835, viadenant, or ZM-241,385). In some embodiments, the immunotherapy is an A2B adenosine inhibitor (e.g., ATL-801, CVT-6883, MRS-1706, MRS-1754, OSIP-339,391, PSB-603, PSB-0788, or PSB-1115). In some embodiments, the immunotherapy is an A3A adenosine inhibitor (e.g., ,KF-26777、MRS-545、MRS-1191、MRS-1220、MRS-1334、MRS-1523、MRS-3777、MRE-3005-F20、MRE-3008-F20、PSB-11、OT-7999、VUF-5574 or SSR 161421). In some embodiments, the immunotherapy is an arginase inhibitor (e.g., arginase antibody, (2S) - (+) -amino-5-iodoacetamido pentanoic acid, NG-hydroxy-L-arginine, (2S) - (+) -amino-6-iodoacetamido hexanoic acid, or (R) -2-amino-6-dihydroxyboryl-2- (2- (piperidin-1-yl) ethyl) hexanoic acid). In some embodiments, the immunotherapy is an HDAC inhibitor (e.g., valproic acid, SAHA, or romidepsin).
In some embodiments, the immunotherapy is a CD-161 (also known as KLRB1 or NKR-P1A) inhibitor (e.g., IMT-009). In some embodiments, the immunotherapy is NK and T cell modulators (e.g., IMT-073).
In some embodiments, an effective amount of an agent that decreases BRM and/or BRG1 levels and/or activity (e.g., decreases activity levels by at least 5%, at least 10%, at least 20%, at least 50%, at least 70%, at least 90%, at least 95%, at least 99%) in a subject is an amount effective to increase activated T cell levels in the subject (e.g., a tumor microenvironment).
In some embodiments, the cancer expresses BRG1 and/or BRM proteins, and/or the cell or subject has been identified as expressing BRG1 and/or BRM. In some embodiments, the cancer expresses BRG1 protein, and/or the cell or subject has been identified as expressing BRG1. In some embodiments, the cancer expresses BRM proteins, and/or the cell or subject has been identified as expressing BRM. In some embodiments, the subject or cancer has and/or has been identified as having a BRG1 loss-of-function mutation. In some embodiments, the subject or cancer has and/or has been identified as having a BRM loss-of-function mutation.
In some embodiments of any of the foregoing methods, the cancer has or has been determined to have one or more BRG1 mutations (e.g., homozygous mutation (homozygous mutation)). In some embodiments, the one or more BRG1 mutations comprise a mutation of the atpase catalytic domain of the protein. In some embodiments, the one or more BRG1 mutations comprise a deletion at the C-terminus of BRG 1.
In some embodiments of any of the foregoing methods, the cancer has or has been determined to have no Epidermal Growth Factor Receptor (EGFR) mutation. In some embodiments of any of the foregoing methods, the cancer has or has been determined to have no Anaplastic Lymphoma Kinase (ALK) driver mutations. In some embodiments of any of the foregoing methods, the cancer has or has been determined to have a KRAS mutation.
In some embodiments, the cancer has or has been determined to have a GNAQ mutation. In some embodiments, the cancer has or has been determined to have a GNA11 mutation. In some embodiments, the cancer has or has been determined to have a PLCB4 mutation. In some embodiments, the cancer has or has been determined to have a CYSLTR mutation. In some embodiments, the cancer has or has been determined to have a BAP1 mutation. In some embodiments, the cancer has or has been determined to have an SF3B1 mutation. In some embodiments, the cancer has or has been determined to have an EIF1AX mutation. In some embodiments, the cancer has or has been determined to have TFE3 translocation. In some embodiments, the cancer has or has been determined to have TFEB translocation. In some embodiments, the cancer has or has been determined to have MITF translocation. In some embodiments, the cancer has or has been determined to have an EZH2 mutation. In some embodiments, the cancer has or has been determined to have a SUZ12 mutation. In some embodiments, the cancer has or has been determined to have an EED mutation.
In some embodiments, the cancer is metastatic. For example, cancer includes cells that exhibit migration and/or invasion of migrating cells, and/or cells that exhibit endothelial cell recruitment and/or angiogenesis. Metastatic cancer may spread by surface sowing in the peritoneal, pleural, pericardial or subarachnoid spaces. Alternatively, metastatic cancer may spread through the lymphatic system or blood-borne. In some embodiments, the cancer is a cell-migrating cancer (e.g., a non-metastatic cell-migrating cancer).
In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, primary focus-unknown tumor, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal gastric cancer (esophagogastric cancer), esophageal cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenal cortex cancer, appendiceal cancer, small intestine cancer, penile cancer, bone cancer, or hematological cancer. In some embodiments of any of the foregoing methods, the cancer is esophageal cancer.
In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, primary unknown tumor, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, penile cancer, bone cancer, renal cell cancer, prostate cancer, or hematological cancer. In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer.
In some embodiments of any of the foregoing methods, the cancer is melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer.
In some embodiments, the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a hematological cancer (e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myelogenous leukemia, myelodysplastic syndrome, immunoglobulin a lambda myeloma, diffuse mixed histiocyte and lymphocyte lymphoma, B-cell lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-hodgkin's lymphoma). In some embodiments, the cancer is breast cancer (e.g., ER positive breast cancer, ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer). In some embodiments, the cancer is bone cancer (e.g., ewing's sarcoma). In some embodiments, the cancer is a renal cell carcinoma (e.g., microphthalmia transcription factor (MITF) family translocator renal cell carcinoma (tRCC)).
In some embodiments of any of the foregoing methods, the cancer is resistant (e.g., the cancer has been determined or is likely to be resistant to a chemotherapeutic or cytotoxic agent, such as by a genetic marker, or is likely to be resistant to a chemotherapeutic or cytotoxic agent, such as a cancer that fails to respond to a chemotherapeutic or cytotoxic agent), and/or fails to respond to a prior therapy (e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, thermotherapy, or photocoagulation, or a combination thereof).
In some embodiments, the cancer is resistant to and/or fails to respond to the following therapies: vitamin Mo Feini, dacarbazine, CTLA4 inhibitors, PD-1 inhibitors, interferon therapy, BRAF inhibitors, MEK inhibitors, radiation therapy, temozolomide, irinotecan, CAR-T therapy, herceptin, panet (perjeta), tamoxifen, hiloda, docetaxel, platinum agents (such as carboplatin), taxanes (such as paclitaxel and docetaxel), ALK inhibitors, MET inhibitors, bicalutamide, abraxane, doxorubicin, gemcitabine, avastin (avastin), sea Le Wei (halaven), lenatinib, PARP inhibitors, brilaNernst (brilanestrant), mTOR inhibitors, topotecan, health (gemzar), VEGFR2 inhibitors, folic acid receptor antagonists, denciclesonide, combretastatin (fosbretabulin), CD-161 inhibitors, or PD-L1 inhibitors, or combinations thereof.
In some embodiments of any of the foregoing methods, the cancer is resistant to and/or fails to respond to: dacarbazine, temozolomide, cisplatin, trosoxaflutamide, fotemustine, IMCgp, CTLA-4 inhibitors (e.g., ipilimumab), PD-1 inhibitors (e.g., nivolumab or pamglizumab), PD-L1 inhibitors (e.g., atilizumab, abamectin (avelumab) or Devaluzumab (durvalumab)), mitogen-activated protein kinase (MEK) inhibitors (e.g., semantenib (selumetinib), bimatinib (binimetinib) or trimetinib (tametinib)), and/or Protein Kinase C (PKC) inhibitors (e.g., cord Qu Tuolin (sotrastaurin) or IDE 196).
In some embodiments of any of the foregoing methods, the cancer is resistant to and/or fails to respond to a previously administered therapy (e.g., a MEK inhibitor or a PKC inhibitor) for treating uveal melanoma. For example, in some embodiments, the cancer is resistant to and/or fails to respond to a mitogen-activated protein kinase (MEK) inhibitor (e.g., semanteme, bimatinib, or trimetinib) and/or a Protein Kinase C (PKC) inhibitor (e.g., cord Qu Tuolin or IDE 196).
In some embodiments, the agent that reduces BRD7 levels and/or activity of a cell is a small molecule compound, antibody, enzyme, and/or polynucleotide.
In some embodiments, the agent that reduces BRD7 levels and/or activity of the cell is an enzyme. In some embodiments, the enzyme is a regularly spaced clustered short palindromic repeats (CRISPR) -associated protein, a Zinc Finger Nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), or a meganuclease. In some embodiments, the CRISPR-associated protein is CRISPR-associated protein 9 (Cas 9).
In some embodiments, the agent that decreases BRM/BRG1 levels and/or activity of the cell is a polynucleotide. In some embodiments, the polynucleotide is an antisense nucleic acid, short interfering RNA (siRNA), short hairpin RNA (shRNA), microrna (miRNA), CRISPR/Cas 9 nucleotide (e.g., guide RNA (gRNA)), or ribozyme. In some embodiments, the agent that decreases BRM/BRG1 levels and/or activity of the cell is a small molecule compound (e.g., a small molecule BRM and/or BRG1 inhibitor, such as a BRM and/or BRG1 inhibitor that is selective for BRM over BRG1 and/or selective for BRG1 over BRM). In some embodiments, the small molecule compound is a degradant.
In some embodiments, the agent that reduces the level and/or activity of BRM/BRG1 is N- (1- ((4- (6- (2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, having the structure:
in some embodiments, the agent that reduces the level and/or activity of BRM/BRG1, or a pharmaceutically acceptable salt thereof, has the structure:
in some embodiments, the agent that reduces the level and/or activity of BRM/BRG1, or a pharmaceutically acceptable salt thereof, has the structure:
in some embodiments, the agent that reduces the level and/or activity of BRM/BRG1, or a pharmaceutically acceptable salt thereof, has the structure:
in some embodiments, the method comprises administering a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient.
In some embodiments of any of the foregoing methods, an effective amount of a compound reduces the level and/or activity of BRG1 by at least 5% (e.g., at least 6%, at least 7%, at least 8%, at least 9%, 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%, at least 90%, at least 95%, or at least 99%) as compared to a reference.
In some embodiments of any of the foregoing methods, an effective amount of the compound reduces the level and/or activity of BRG1 by at least 5% (e.g., at least 6%, at least 7%, at least 8%, at least 9%, 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%, at least 90%, at least 95%, or at least 99%) compared to a reference for at least 12 hours (e.g., at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, at least 22 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 14 days, at least 21 days, at least 28 days, or longer).
In some embodiments of any of the foregoing methods, an effective amount of the compound reduces the level and/or activity of BRM by at least 5% (e.g., at least 6%, at least 7%, at least 8%, at least 9%, 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%, at least 90%, at least 95%, or at least 99%) as compared to a reference.
In some embodiments of any of the foregoing methods, an effective amount of the compound reduces the level and/or activity of BRM by at least 5% (e.g., at least 6%, at least 7%, at least 8%, at least 9%, 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%, at least 90%, at least 95%, or at least 99%) compared to a reference for at least 12 hours (e.g., at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, at least 22 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 14 days, at least 21 days, at least 28 days, or longer).
In some embodiments, an effective amount of a compound of the invention is an amount effective to inhibit metastasis colonization of the liver and/or brain by cancer (METASTATIC COLONIZATION).
In another embodiment of any of the foregoing methods, the method further comprises administering to the subject an additional anti-cancer therapy, e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, thermotherapy, or photocoagulation, or a combination thereof. In some embodiments, the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, e.g., an antimetabolite, an antimitotic agent, an antitumor antibiotic, an asparagine-specific enzyme, a bisphosphonate, an antitumor agent, an alkylating agent, a DNA repair enzyme inhibitor, a histone deacetylase inhibitor, a corticosteroid, a demethylating agent, an immunomodulator, a janus-associated kinase inhibitor, a phosphoinositide 3 kinase inhibitor, a proteasome inhibitor, or a tyrosine kinase inhibitor, or a combination thereof.
In some embodiments, the compounds of the invention are used in combination with another anti-cancer therapy (such as surgery, a MEK inhibitor and/or a PKC inhibitor, or a combination thereof) for the treatment of uveal melanoma. For example, in some embodiments, the methods further comprise performing a surgical procedure before, after, or simultaneously with the administration of the compounds of the invention. In some embodiments, the methods further comprise administering a MEK inhibitor (e.g., semanteme, bimatinib, or trimetinib) and/or a PKC inhibitor (e.g., cable Qu Tuolin or IDE 196) before, after, or simultaneously with administration of a compound of the invention.
In some embodiments, the anti-cancer therapy and the compound of the invention are administered within 28 days (e.g., within 21 days, within 14 days, or within 7 days) of each other and each in an amount effective together to treat the subject.
In particular embodiments, the antiproliferative agent is: chemotherapeutic or cytotoxic agents, differentiation inducing agents (e.g., retinoic acid, vitamin D, cytokines), hormonal agents, immune agents, or anti-angiogenic agents. Chemotherapeutic and cytotoxic agents include, but are not limited to, alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposide, and other agents (e.g., paclitaxel, taxol, docetaxel, taxotere (taxotere), cisplatin). A list of additional compounds with antiproliferative activity can be found in L.Brunton, B.Chabner and b.knollman (editions), goodman and GILMAN THE Pharmacological Basis of Therapeutics, twelfth edition, 2011,McGraw Hill Companies,New York,NY.
The method may further comprise administering an antiproliferative agent selected from the group consisting of: alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotics, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyl transferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloprotease inhibitors, ribonucleoside reductase inhibitors, tnfα agonists/antagonists, endothelin a receptor antagonists, retinoic acid receptor agonists, immunomodulators, hormonal and anti-hormonal agents, photodynamic agents (photodynamic agent), tyrosine kinase inhibitors, antisense compounds, corticosteroids, HSP90 inhibitors, proteasome inhibitors (e.g., NPI-0052), CD40 inhibitors, anti-CSI antibodies, FGFR3 inhibitors, VEGF inhibitors, MEK inhibitors, cyclin D1 inhibitors, NF-kB inhibitors, anthracyclines, histone deacetylases, kinesin (kinesin) inhibitors, phosphatase inhibitors, COX2 inhibitors, mTOR inhibitors, calcineurin antagonists, IMiD, or other agents for the treatment of proliferative diseases.
In particular embodiments, the antiproliferative agent and/or the immunotherapeutic and the agent that reduces the level and/or activity of BRM and/or BRG1 are administered within 28 days (e.g., within 21, 14, 10, 7, 5, 4, 3, 2, or 1 days) or within 24 hours (e.g., 12, 6, 3, 2, or 1 hours; or concomitantly) of each other, each in an amount effective together to treat the subject.
In another aspect, the invention features an agent (e.g., an agent described herein) that reduces the level and/or activity of BRM and/or BRG1, for use in combination with an immunotherapy (e.g., an immunotherapy described herein) to treat a cancer (e.g., a cancer described herein) in a subject in need thereof, e.g., according to a method described herein.
In yet another aspect, the invention features a compound having the structure:
Or a pharmaceutically acceptable salt thereof, for use in combination with an immunotherapy (e.g., an immunotherapy as described herein) to treat a cancer (e.g., a cancer as described herein) in a subject in need thereof, e.g., according to a method as described herein.
In another aspect, the invention features the use of an agent that reduces the level and/or activity of BRM and/or BRG1 (e.g., an agent described herein) in combination with immunotherapy (e.g., an immunotherapy described herein) to manufacture a medicament for treating cancer (e.g., a cancer described herein) in a subject in need thereof, e.g., according to a method described herein.
In yet another aspect, the invention features a compound having the structure:
Or a pharmaceutically acceptable salt thereof, in combination with an immunotherapy (e.g., an immunotherapy as described herein) to manufacture a medicament for treating a cancer (e.g., a cancer as described herein) in a subject in need thereof, e.g., according to a method as described herein.
Chemical terminology
The compounds of the invention may have one or more asymmetric carbon atoms and may exist as optically pure enantiomers, mixtures of enantiomers (such as, for example, racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates. Optically active forms can be obtained, for example, by resolution of the racemate, by asymmetric synthesis or asymmetric chromatography (chromatography using chiral adsorbents or eluents). That is, certain disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are non-overlapping, most often because they contain asymmetrically substituted carbon atoms as chiral centers. "enantiomer" means one of a pair of molecules that are mirror images of each other and that are non-overlapping. Diastereomers are stereoisomers that are not in mirror relationship, most often because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound may be prepared, for example, by separating the enantiomer from the racemate using one or more well-known techniques and methods such as, for example, chiral chromatography and separation methods based thereon. One skilled in the art can readily determine the appropriate techniques and/or methods for separating enantiomers of compounds described herein from a racemic mixture. "racemate" or "racemic mixture" means a compound containing two enantiomers, wherein such mixture does not exhibit optical activity; i.e. they do not rotate the plane of polarized light. "geometric isomer" means an isomer in which the orientation of the substituent atoms relative to the carbon-carbon double bond, cycloalkyl ring, or bridged bicyclic ring system is different. The atoms on each side of the carbon-carbon double bond (except H) may be in the E (substituents on opposite sides of the carbon-carbon double bond) or Z (substituents oriented on the same side) configuration. "R", "S", "R", "E", "Z", "cis" and "trans" refer to configuration relative to the core molecule. Some of the disclosed compounds may exist in atropisomer forms. Atropisomers are stereoisomers produced by the blockage of rotation about a single bond, where the rotational spatial strain barrier is high enough to allow separation of conformational isomers. The compounds of the invention may be prepared as individual isomers by isomer specific synthesis or resolution from mixtures of isomers. Conventional resolution techniques include formation of a salt of the free base of each isomer of the isomer pair using an optically active acid (then fractional crystallization and regeneration of the free base), formation of a salt of the acid form of each isomer of the isomer pair using an optically active amine (then fractional crystallization and regeneration of the free acid), formation of an ester or amide of each isomer of the isomer pair using an optically pure acid, amine or alcohol (then chromatographic separation and removal of chiral auxiliary), or resolution of an isomer mixture of the starting material or end product using various well known chromatographic methods. When the stereochemistry of the disclosed compounds is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure by weight. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight. The percent optical purity is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer to the weight of all diastereomers. When the stereochemistry of the disclosed compounds is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure relative to the other stereoisomers by mole fraction. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by mole fraction. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by mole fraction. The percent purity in mole fraction is the ratio of the moles of enantiomer to the moles of enantiomer plus the moles of optical isomer thereof. Similarly, the percent purity in mole fraction is the ratio of the moles of diastereomers to the moles of diastereomers plus the moles of isomers thereof. When a disclosed compound is named or depicted by structure without indicating stereochemistry and the compound has at least one chiral center, it is to be understood that the name or structure encompasses one enantiomer of the compound that does not contain the corresponding optical isomer, a racemic mixture of the compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses diastereomers that are free of other diastereomers, numerous diastereomers that are free of other diastereomers, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomers, or mixtures of diastereomers in which one or more diastereomers are enriched relative to the other diastereomers. The present invention encompasses all such forms.
Unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、32P、33P、35S、18F、36Cl、123I and 125 I. Isotopically-labeled compounds (e.g., those labeled with 3 H and 14 C) are useful in compound or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon 14 (i.e., 14 C) isotopes are useful for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced with 2 H or 3 H, or one or more carbon atoms are replaced with 13 C or 14 C enriched carbon. Positron emitting isotopes such as 15O、13N、11 C and 18 F are useful in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy (substrate receptor occupancy). The preparation of isotopically-labeled compounds is known to those skilled in the art. For example, isotopically-labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the invention described herein by substituting a non-isotopically-labeled reagent with an isotopically-labeled reagent.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for the present disclosure are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
Definition of the definition
In the present application, unless the context clearly indicates otherwise, (i) the term "a/an" may be understood to mean "at least one" unless the context clearly indicates otherwise; (ii) The term "or/and" may be understood to mean "and/or"; and (iii) the terms "comprising" and "comprises" are to be understood to cover the listed components or steps as such, whether by itself or with one or more additional components or steps.
As used herein, the term "A1 adenosine inhibitor" refers to a compound, such as an antibody, capable of inhibiting the activity of a protein encoded by the ADORA1 gene (accession No. P3042) in humans. Known A1 adenosine inhibitors include 8-cyclopentyl-1, 3-dimethylxanthine, 8-cyclopentyl-1, 3-dipropylxanthine, 8-phenyl-1, 3-dipropylxanthine, palmitoleine, BG-9719, BG-9928, FK-453, FK-838, luo Ge theophylline and N-0861.
As used herein, the term "A2A adenosine inhibitor" refers to a compound, such as an antibody, capable of inhibiting the activity of a protein encoded by the ADORA2A gene (accession number P29274) in humans. Known A2A adenosine inhibitors include ATL-4444, itrafylline, MSX-3, readnan, SCH-58261, SCH-412,348, SCH-442,416, ST-1535, VER-6623, VER-6947, VER-7835, viadenant and ZM-241,385.
As used herein, the term "A2B adenosine inhibitor" refers to a compound, such as an antibody, capable of inhibiting the activity of a protein encoded by the ADORA2B gene (accession number P29275) in humans. Known A2B adenosine inhibitors include ATL-801, CVT-6883, MRS-1706, MRS-1754, OSIP-339,391, PSB-603, PSB-0788, and PSB-1115.
As used herein, the term "A3A adenosine inhibitor" refers to a compound, such as an antibody, capable of inhibiting the activity of a protein encoded by the ADORA3 gene (accession number P0DMS 8) in humans. Known A3A adenosine inhibitors include KF-26777、MRS-545、MRS-1191、MRS-1220、MRS-1334、MRS-1523、MRS-3777、MRE-3005-F20、MRE-3008-F20、PSB-11、OT-7999、VUF-5574 and SSR161421.
As used herein, the terms "about" and "approximately" refer to values within 10% of the values described. For example, the term "about 5nM" means a range of 4.5 to 5.5 nM.
As used herein, the term "administering" refers to administering a composition (e.g., a compound or a preparation comprising a compound as described herein) to a subject or system. Administration to an animal subject (e.g., human) can be by any suitable route. For example, in some embodiments, administration may be transbronchial (including by bronchial instillation), buccal, enteral, intradermal (interdermal), intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, transmucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, transtracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal (vitreal).
As used herein, the term "arginase inhibitor" refers to a compound capable of inhibiting the activity of a protein encoded by the ARG1 (accession number P05089) or ARG2 gene (accession number P78540) in a human. Known arginase inhibitors include (2S) - (+) -amino-5-iodoacetamido pentanoic acid, NG-hydroxy-L-arginine, (2S) - (+) -amino-6-iodoacetamido hexanoic acid or (R) -2-amino-6-dihydroxyboryl-2- (2- (piperidin-1-yl) ethyl) hexanoic acid.
As used herein, the term "BAF complex" refers to BRG1 or HBRM related factor complex in human cells.
As used herein, the term "BAF complex phase Guan Bingzheng" refers to a condition that is caused or affected by the activity level of the BAF complex.
As used herein, the term "BRG1 loss-of-function mutation" refers to a mutation in BRG1 that results in a decrease in protein activity (e.g., a decrease in BRG1 activity of at least 1%, e.g., a decrease in BRG1 activity of 2%, 5%, 10%, 25%, 50%, or 100%). Exemplary BRG1 loss-of-function mutations include, but are not limited to, homozygous BRG1 mutations and deletions at the C-terminus of BRG 1.
As used herein, the term "BRG1 loss of function disorder" refers to a disorder (e.g., cancer) that exhibits reduced BRG1 activity (e.g., reduced BRG1 activity by at least 1%, e.g., reduced BRG1 activity by 2%, 5%, 10%, 25%, 50%, or 100%).
The term "cancer" refers to disorders caused by malignant neoplastic cell proliferation, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.
As used herein, "combination therapy" or "combined administration" means administration of two (or more) different agents or treatments to a subject as part of a defined treatment regimen for a particular disease or disorder. The treatment regimen defines the dose and period of administration of each agent such that the effects of the individual agents on the subject overlap. In some embodiments, delivery of two or more agents is simultaneous or synchronized and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, the combined administration of two or more agents or treatments results in a reduction in symptoms or other parameters associated with the disorder that is greater than the reduction observed with one agent or treatment delivered alone or in the absence of the other agent or treatment. The effect of the two treatments may be partial addition, complete addition, or greater than addition (e.g., synergy). Sequential or substantially simultaneous administration of each therapeutic agent may be accomplished by any suitable route including, but not limited to, oral route, intravenous route, intramuscular route, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by different routes. For example, a first therapeutic agent in combination may be administered by intravenous injection, while a second therapeutic agent in combination may be administered orally.
As used herein, the term "CTLA-4 inhibitor" refers to a compound, such as an antibody, capable of inhibiting the activity of a protein encoded by a CTLA4 gene in a human. Known CTLA-4 inhibitors include ipilimumab.
As used herein, the term "CSF-1R inhibitor" refers to a compound, such as an antibody, capable of inhibiting the activity of a protein encoded by the CSF1R gene (accession number P07333) in a human. Known CSF-1R inhibitors include pexidanib or AZD6495.
"Determining" the "level of a protein or RNA means directly or indirectly detecting the protein or RNA by methods known in the art. "directly determining" means performing a process (e.g., assaying or testing a sample or "analyzing a sample," as that term is defined herein) to obtain a physical entity or value. "indirectly determining" refers to receiving a physical entity or value from another party or source (e.g., a third party laboratory that directly obtains the physical entity or value). Methods of measuring protein levels generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assays (ELISA), radioimmunoassays (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescence polarization, phosphorescence, immunohistochemical analysis, matrix assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry, liquid Chromatography (LC) mass spectrometry, microcytometry (microcytometry), microscopy, fluorescence Activated Cell Sorting (FACS) and flow cytometry, as well as assays based on protein characteristics including, but not limited to, enzymatic activity or interactions with other protein partners (protein partners). Methods of measuring RNA levels are known in the art and include, but are not limited to, quantitative polymerase chain reaction (qPCR) and northern blot analysis.
By "reduced level" or "increased level" of a protein or RNA, it is meant that the level of the protein or RNA, respectively, is reduced or increased by more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500% or more, or by more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100% or about 200%, or by less than about 0.01%, about 0.02%, about 0.1, about 0.3, about 0.5, about 0.8 or less, or by more than about 1.2, about 1.4, about 1.8, about 2.0, about 3.0, about 3.5, about 4.5, about 5, about 10, about 40, about 30, about 100%, or more than about 100%, or more, as compared to a reference. The level of protein may be expressed in terms of mass/volume (e.g., g/dL, mg/mL, μg/mL, ng/mL) or as a percentage relative to the total protein in the sample.
By "reducing the activity of BAF complex" is meant reducing the level of activity associated with BAF complex or associated downstream effects. A non-limiting example of reducing the activity of BAF complexes is Sox2 activation. The activity level of BAF complex can be measured using any method known in the art, for example, the method described in Kadoch et al, cell,2013, 153,71-85, which method is incorporated herein by reference.
As used herein, the term "derivative" refers to naturally occurring, synthetic, and semisynthetic analogs of a compound, peptide, protein, or other substance described herein. Derivatives of the compounds, peptides, proteins, or other substances described herein may retain or improve the biological activity of the starting material.
As used herein, "determining a resistant" cancer refers to a cancer that is resistant based on non-responsiveness or reduced responsiveness to a chemotherapeutic agent, or a cancer that is predicted to be resistant based on a prognostic assay (e.g., a gene expression assay).
"Drug resistance" means a cancer that does not respond to or exhibits reduced response to one or more chemotherapeutic agents (e.g., any of the agents described herein).
As used herein, the term "failing to respond to a prior therapy" or "refractory to a prior therapy" refers to a cancer that progresses despite treatment with the therapy.
As used herein, the term "HDAC inhibitor" refers to a compound, such as an antibody, capable of inhibiting the activity of a protein that is a member of the histone deacetylase class of enzymes (e.g., ,HDAC1、HDAC2、HDAC3、HDAC4、HDAC5、HDAC6、HDAC7、HDAC8、HDAC9、HDAC10、HDAC11、SIRT1、SIRT2、SIRT3、SIRT4、SIRT5、SIRT6 and SIRT 7). Known HDAC inhibitors include valproic acid, SAHA and romidepsin.
As used herein, the term "IDO inhibitor" refers to a compound, such as an antibody, capable of inhibiting the activity of a protein encoded by the IDO1 gene (accession P14202) in humans. Known IDO inhibitors include nor Ha Erman, rosmarinic acid and α -methyl-tryptophan.
As used herein, the terms "inhibit BRM" and/or "inhibit BRG1" refer to blocking or reducing the level or activity of an atpase catalytic binding domain or bromodomain of a protein. BRM and/or BRG1 inhibition may be determined using methods known in the art, for example, BRM and/or BRG1 atpase assays, nano DSF assays, or BRM and/or BRG1 luciferase cell assays.
As used herein, the term "LXS196", also known as IDE196, refers to PKC inhibitors having the following structure:
Or a pharmaceutically acceptable salt thereof.
As used herein, "metastatic nodules" refers to the accumulation of tumor cells in the body at sites other than the site of the primary tumor.
As used herein, "metastatic cancer" refers to a tumor or cancer in which cancer cells forming the tumor have a high potential or have begun to metastasize or spread from one location to another location or locations within the subject (e.g., to produce a secondary tumor within the subject) by the lymphatic system or by hematogenous spread. This metastatic behaviour may be predictive of malignancy. In some cases, metastatic behavior may be associated with an increase in cell migration and/or invasion behavior of tumor cells.
Examples of cancers that may be defined as metastatic include, but are not limited to, lung cancer (e.g., non-small cell lung cancer), breast cancer, ovarian cancer, colorectal cancer, biliary tract cancer, bladder cancer, brain cancer (including glioblastoma and medulloblastoma (medullablastomas)), cervical cancer, choriocarcinoma, endometrial cancer, esophageal cancer, gastric cancer, hematological tumors, multiple myeloma, leukemia, intraepithelial tumors, liver cancer, lymphoma, neuroblastoma, oral cancer, pancreatic cancer, prostate cancer, sarcomas, skin cancer (including melanoma), basal cell carcinoma, squamous cell carcinoma, testicular cancer, stromal tumors, germ cell tumors, thyroid cancer, and renal cancer.
As used herein, "non-metastatic cell-migrating cancer" refers to cancer that does not migrate through the lymphatic system or through hematogenous diffusion.
As used herein, the term "PD-1 inhibitor" refers to a compound, such as an antibody, capable of inhibiting the activity of a protein encoded by the PDCD1 gene in a human. Known PD-1 inhibitors include nal Wu Shankang, palbociclizumab, pilizumab, BMS 936559 and actigraphy Li Zhushan.
As used herein, the term "PD-L1 inhibitor" refers to a compound, such as an antibody, capable of inhibiting the activity of a protein encoded by the CD274 gene in humans. Known PD-L1 inhibitors include atilizumab or Dewaruzumab.
As used herein, the term "pharmaceutical composition" represents a composition containing a compound described herein formulated with pharmaceutically acceptable excipients and suitable for administration to a mammal (e.g., a human). Typically, pharmaceutical compositions are approved by a government regulatory agency for manufacture or sale as part of a therapeutic regimen for treating a disease in a mammal. The pharmaceutical composition may be formulated, for example, for oral administration in unit dosage form (e.g., tablet, capsule, caplet, gel capsule, or syrup); for topical application (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution in a solvent system that is free of particulate embolization and suitable for intravenous use); or any other pharmaceutically acceptable formulation.
As used herein, "pharmaceutically acceptable excipient" refers to any ingredient (e.g., a vehicle capable of suspending or dissolving an active compound) other than the compounds described herein and having substantially non-toxic and non-inflammatory properties in a patient. Excipients may include, for example: anti-tackifiers, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), softeners, emulsifiers, fillers (diluents), film formers or coatings, fragrances, flavoring agents, glidants (flow enhancers), lubricants, preservatives, printing inks (PRINTING INK), adsorbents, suspending or dispersing agents, sweeteners, and hydration water.
As used herein, the term "pharmaceutically acceptable salt" means any pharmaceutically acceptable salt of a compound described herein. Pharmaceutically acceptable salts of any of the compounds described herein may include those salts which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al, J.pharmaceutical Sciences 66:1-19,1977 and Pharmaceutical Salts: properties, selection, and Use, (P.H.Stahl and C.G.Wermuth editions), wiley-VCH, 2008. These salts may be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base groups with a suitable organic acid.
The compounds of the present invention may have an ionizable group so as to be capable of being prepared as a pharmaceutically acceptable salt. These salts may be, for example, acid addition salts involving inorganic or organic acids, or in the case of the acidic form of the compounds of the invention, the salts may be prepared from inorganic or organic bases. Typically, the compounds are prepared or used as pharmaceutically acceptable salts, which are prepared as pharmaceutically acceptable acid or base addition products. Suitable pharmaceutically acceptable acids and bases and methods for preparing the appropriate salts are well known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases.
As used herein, "progression free survival" refers to the length of time that the disease (e.g., cancer) being treated does not worsen during and after the drug or treatment.
As used herein, "proliferation" refers to the replication or increase of a similar form (cell) due to constituent (cell) elements.
By "reducing the activity of BRM and/or BRG 1" is meant reducing the level of activity associated with BRM and/or BRG1 or associated downstream effects. The level of BRM and/or BRG1 activity may be measured using any method known in the art. In some embodiments, the agent that decreases the activity of BRM and/or BRG1 is a small molecule BRM and/or BRG1 inhibitor. In some embodiments, the agent that reduces the activity of BRM and/or BRG1 is a small molecule BRM and/or BRG1 degrading agent.
By "reducing the level of BRM and/or BRG 1" is meant reducing the level of BRM and/or BRG1 in a cell or subject, for example, by administering a degrading agent to the cell or subject. The level of BRM and/or BRG1 may be measured using any method known in the art.
"Reference" means any useful reference for comparing protein or RNA levels. The reference may be any sample, standard curve or level used for comparison purposes. The reference may be a normal reference sample or a reference standard or level. The "reference sample" may be, for example, a control, e.g., a predetermined negative control value, such as a "normal control" or a previous sample taken from the same subject; a sample from a normal healthy subject, such as normal cells or normal tissue; a sample (e.g., a cell or tissue) from a subject not suffering from a disease; a sample from a subject diagnosed with a disease but not yet treated with a compound of the invention; a sample from a subject that has been treated with a compound of the invention; or a sample of purified protein or RNA (e.g., any of the proteins or RNAs described herein) at a known normal concentration. "reference standard or level" means a value or number derived from a reference sample. A "normal control value" is a predetermined value that represents a non-disease state, such as an expected value for a healthy control subject. Typically, the normal control value is expressed as a range ("between X and Y"), a high threshold ("no higher than X") or a low threshold ("no lower than X"). Subjects with a measurement that is within the normal control value for a particular biomarker are generally referred to as being "within the normal limits" for that biomarker. The normal reference standard or level may be derived from a normal subject not suffering from a disease or disorder (e.g., cancer); values or numbers of subjects that have been treated with the compounds of the invention. In preferred embodiments, the reference sample, standard or level is matched to the sample of the sample subject by at least one of the following criteria: age, weight, sex, stage of disease and general health. Standard curves for purified protein or RNA (e.g., any of the proteins or RNAs described herein) levels within normal reference ranges may also be used as references.
As used herein, the term "selective for BRM over BRG 1" means that a compound inhibits BRM at least 5% (e.g., at least 10%, at least 25%, at least 50%, at least 75%, or at least 100%) greater than the level and/or activity of a compound inhibits BRG 1.
As used herein, the term "selective for BRG1 over BRM" means that a compound inhibits BRG1 at least 5% (e.g., at least 10%, at least 25%, at least 50%, at least 75%, or at least 100%) greater than the level and/or activity of a compound inhibits BRM.
As used herein, "slowing the diffusion of metastasis" refers to reducing or stopping the formation of new sites; or reduce, stop or reverse tumor burden.
As used herein, the term "subject" refers to any organism to which a composition according to the invention may be administered, e.g., for experimental, diagnostic, prophylactic and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). The subject may seek or need treatment, require treatment, be receiving treatment in the future, or the subject is a human or animal being treated for a particular disease or condition by a trained professional.
As used herein, the term "treatment" or "treatment" means a therapeutic treatment or any measure whose purpose is to slow down (alleviate) an undesired physiological condition, disorder or disease or to obtain a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; a reduction in the extent of a disorder, condition or disease; the condition, disorder or disease state is stable (i.e., not worsening); delay the onset or slowing of the onset of a disorder, condition, or disease progression; improvement or alleviation of a condition, disorder, or disease state (whether partial or complete); an improvement in at least one measurable physical parameter, but not necessarily noticeable to the patient; or enhancement or amelioration of a disorder, condition, or disease. Treatment involves eliciting a clinically significant response without undue side effects. Treatment also includes extending survival compared to expected survival without treatment. The compounds of the invention are also useful for "prophylactically treating" or "preventing" a disorder in a subject, for example, who is at increased risk of developing the disorder.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for the present disclosure are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
A detailed description of one or more embodiments of the invention is set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.
Drawings
FIG. 1 is a graph showing inhibition of cell proliferation of a number of cancer cell lines by BRG1/BRM inhibitor (Compound A).
FIG. 2 is a graph showing inhibition of cell proliferation of uveal melanoma cell line 92-1 by BRG1/BRM inhibitors (Compound A), MEK inhibitors (semtinib), and PKC inhibitors (LXS 196).
FIG. 3 is a graph showing inhibition of cell proliferation of the uveal melanoma cell line MP41 by BRG1/BRM inhibitor (Compound A), MEK inhibitor (semtinib), and PKC inhibitor (LXS 196).
FIG. 4 is a graph showing inhibition of cell proliferation of a number of cancer cell lines by a BRG1/BRM inhibitor (Compound B).
FIG. 5 is a graph showing the Area Under Curve (AUC) calculated from the dose response curve of a cancer cell line treated with a BRG1/BRM inhibitor (Compound B).
FIG. 6 is a graph showing inhibition of cell proliferation of uveal melanoma and non-small cell lung cancer cell lines by BRG1/BRM inhibitors (Compound B).
FIG. 7 is a graph showing inhibition of cell proliferation of uveal melanoma cell line 92-1 by BRG1/BRM inhibitors (Compound B), MEK inhibitors (semtinib), and PKC inhibitors (LXS 196).
FIG. 8 is a graph showing inhibition of cell proliferation of the uveal melanoma cell line MP41 by BRG1/BRM inhibitor (Compound B), MEK inhibitor (semtinib), and PKC inhibitor (LXS 196).
Fig. 9 is a graph showing inhibition of cell proliferation by PKC inhibitor (LXS 196) on parental and PKC inhibitor refractory uveal melanoma cell lines.
FIG. 10 is a graph showing inhibition of cell proliferation by BRG1/BRM inhibitor (Compound B) on parent and PKC inhibitor refractory uveal melanoma cell lines.
FIG. 11 is a graph showing inhibition of tumor growth by BRG1/BRM inhibitor (Compound C) in mice implanted with uveal melanoma cell lines.
FIG. 12 is a graphical representation of tumor size from mice implanted with a uveal melanoma cell line and administered a BRG1/BRM inhibitor (Compound C).
FIG. 13 is a graph showing the change in body weight of mice implanted with a uveal melanoma cell line and administered a BRG1/BRM inhibitor (Compound C).
FIG. 14 is a graph showing inhibition of cell proliferation of N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide on several uveal melanoma cell lines.
Fig. 15 is a graph showing inhibition of tumor growth by N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide in mice implanted with a uveal melanoma cell line.
Fig. 16 is a graph showing the change in body weight of mice implanted with a uveal melanoma cell line and administered N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide.
FIG. 17 is a graph showing tumor growth inhibition with PD-1 inhibitor alone, BRM/BRG1 inhibitor alone, and a combination of PD-1 inhibitor and BRM/BRG1 inhibitor in a B16/F10 homology model.
FIG. 18 is a graph showing tumor growth inhibition in each individual mouse with PD-1 inhibitor alone, BRM/BRG1 inhibitor alone, and a combination of PD-1 inhibitor and BRM/BRG1 inhibitor in a B16/F10 homology model.
FIG. 19 is a graph showing Kaplan-Meier survival curves for each individual mouse with PD-1 inhibitor alone, BRM/BRG1 inhibitor alone, and a combination of PD-1 inhibitor and BRM/BRG1 inhibitor in a B16/F10 isogenic model.
FIG. 20 is a graph showing tumor growth inhibition with PD-1 inhibitor alone, BRM/BRG1 inhibitor alone, and a combination of PD-1 inhibitor and BRM/BRG1 inhibitor in an A20 lymphoma model.
FIG. 21 is a graph showing tumor growth inhibition in an A20 lymphoma model with PD-1 inhibitor alone, BRM/BRG1 inhibitor alone, and each individual mouse with the PD-1 inhibitor in combination with the BRM/BRG1 inhibitor.
FIG. 22 is a graph showing Kaplan-Meier survival curves for each individual mouse with PD-1 inhibitor alone, BRM/BRG1 inhibitor alone, and a combination of PD-1 inhibitor and BRM/BRG1 inhibitor in an A20 lymphoma model.
FIG. 23 is a graph showing tumor growth inhibition with PD-1 inhibitor alone, BRM/BRG1 inhibitor alone, and a combination of PD-1 inhibitor and BRM/BRG1 inhibitor in a CT26 colorectal model.
FIG. 24 is a graph showing tumor growth inhibition in CT26 colorectal models with PD-1 inhibitors alone, BRM/BRG1 inhibitors alone, and each individual mouse of the combination of PD-1 inhibitors and BRM/BRG1 inhibitors.
FIG. 25 is a graph showing Kaplan-Meier survival curves for each individual mouse with PD-1 inhibitor alone, BRM/BRG1 inhibitor alone, and a combination of PD-1 inhibitor and BRM/BRG1 inhibitor in a CT26 colorectal model.
FIG. 26 is a graph showing tumor growth inhibition in CT26 colorectal models with PD-L1 inhibitor alone, BRM/BRG1 inhibitor alone, and each individual mouse of the combination of PD-L1 inhibitor and BRM/BRG1 inhibitor.
FIG. 27 is a graph showing Kaplan-Meier survival curves for each individual mouse with PD-L1 inhibitor alone, BRM/BRG1 inhibitor alone, and a combination of PD-L1 inhibitor and BRM/BRG1 inhibitor in a CT26 colorectal model.
Detailed Description
The inventors have found that inhibition or depletion of BRM and/or BRG1 levels and/or activity of cells is effective in treating cancer in combination with immunotherapy treatment. Thus, the invention features a useful method of treating cancer, for example, in a subject in need thereof.
BRM and/or BRG1 reducing agent
The agents described herein that reduce BRM and/or BRG1 levels and/or activity of a cell may be, for example, antibodies, proteins (such as enzymes), polynucleotides, or small molecule compounds. The agent reduces the level of activity associated with BRM and/or BRG1 or a related downstream effect, or reduces the level of BRM and/or BRG1 in a cell or subject.
In some embodiments, the agent that reduces BRM and/or BRG1 levels and/or activity of the cell is an enzyme, polynucleotide, or small molecule compound, such as a degrading agent or small molecule BRM and/or BRG1 inhibitor.
Antibodies to
The agent that reduces the level and/or activity of BRM and/or BRG1 may be an antibody or antigen binding fragment thereof. For example, an agent that decreases the level and/or activity of BRM and/or BRG1 as described herein is an antibody that decreases or blocks the activity and/or function of BRM and/or BRG1 by binding to BRM and/or BRG 1.
The preparation and use of therapeutic antibodies against target antigens (e.g., BRM and/or BRG 1) is known in the art. See, e.g., references cited above and Zhiqiang An (editions), therapeutic Monoclonal Antibodies: from Bench to clinic 1 st edition, wiley 2009, and Greenfield (editions), antibodies: ALabator Manual (second edition) Cold Spring Harbor Laboratory Press 2013, methods for preparing recombinant Antibodies, including antibody engineering, use of degenerate oligonucleotides, 5' -RACE, phage display, and mutagenesis; antibody testing and characterization; antibody pharmacokinetics and pharmacodynamics; antibody purification and storage; screening and marking techniques.
Polynucleotide
In some embodiments, the agent that decreases the level and/or activity of BRM/BRG1 is a polynucleotide. In some embodiments, the polynucleotide is an inhibitory RNA molecule, e.g., acting through an RNA interference (RNAi) pathway. Inhibitory RNA molecules can reduce the expression level (e.g., protein level or mRNA level) of BRM and/or BRG 1. For example, inhibitory RNA molecules include short interfering RNAs (sirnas), short hairpin RNAs (shrnas), and/or micrornas (mirnas) that target full-length BRMs and/or BRGs 1. siRNA is a double stranded RNA molecule, typically about 19-25 base pairs in length. shRNA is an RNA molecule comprising hairpin turns that reduces expression of a target gene by RNAi. Micrornas are non-coding RNA molecules that are typically about 22 nucleotides in length. MiRNA binds to a target site on an mRNA molecule and silences mRNA, for example, by causing cleavage of mRNA, destabilization of mRNA, or inhibition of mRNA translation. Degradation is caused by enzymatic RNA-induced silencing complex (RISC).
In some embodiments, the agent that decreases the level and/or activity of BRM/BRG1 is an antisense nucleic acid. Antisense nucleic acids include antisense RNA (asRNA) and antisense DNA (asDNA) molecules, typically about 10 to 30 nucleotides in length, that recognize a polynucleotide target sequence or sequence portion by hydrogen bonding interactions with nucleotide bases of the target sequence (e.g., BRM and/or BRG 1). The target sequence may be single-or double-stranded RNA, or single-or double-stranded DNA.
In some embodiments, the polynucleotide reduces the level and/or activity of a functional negative regulator or a functional positive regulator. In other embodiments, the polynucleotide reduces the level and/or activity of an inhibitor of a functional positive regulator.
Polynucleotides may be modified, for example, to contain modified nucleotides, e.g., 2' -fluoro, 2' -o-methyl, 2' -deoxy, unlocked nucleic acid (unlocked nucleic acid), 2' -hydroxy, phosphorothioate, 2' -thiouridine, 4' -thiouridine, 2' -deoxyuridine. Without being bound by theory, it is believed that certain modifications may increase nuclease resistance and/or serum stability, or reduce immunogenicity. The polynucleotides mentioned above may also be provided in a specific form (such as liposomes, microspheres), or may be applied in gene therapy, or may be provided in combination with attached moieties. Such attachment moieties include polycations, such as polylysine, which acts as a charge neutralizer for the phosphate backbone, or hydrophobic moieties, such as lipids (e.g., phospholipids, cholesterol, etc.) that enhance interactions with cell membranes or increase uptake of nucleic acids. These moieties may be attached to the 3 'or 5' end of the nucleic acid, and may also be attached by bases, sugars or intramolecular nucleoside linkages. The other moiety may be a blocking group located specifically at the 3 'or 5' end of the nucleic acid to prevent degradation by nucleases (such as exonucleases, rnases, etc.). Such end capping groups include hydroxy protecting groups known in the art, including diols such as polyethylene glycol and tetraethylene glycol. The inhibition of polynucleotides can be examined in vivo and in vitro using the cell line or animal based gene expression systems of the invention.
In some embodiments, the polynucleotide reduces the level and/or activity or function of BRM and/or BRG 1. In embodiments, the polynucleotide inhibits expression of BRM and/or BRG 1. In other embodiments, the polynucleotide increases BRD7 degradation and/or decreases BRM and/or BRG1 stability (i.e., half-life). Polynucleotides may be chemically synthesized or transcribed in vitro.
Inhibitory polynucleotides can be designed by methods well known in the art. The siRNA, miRNA, shRNA and asRNA molecules having sufficient homology to provide the sequence specificity required for unique degradation of any RNA can be designed using procedures known in the art, including but not limited to those maintained on the website of Thermo FISHER SCIENTIFIC, the german cancer research center, and the vergence medical center at state ohio. A person skilled in the art can routinely conduct systematic testing of several designed species to optimize inhibitory polynucleotide sequences. Considerations in designing interfering polynucleotides include, but are not limited to, biophysical, thermodynamic, and structural considerations, base preference at specific positions of the sense strand, and homology. The preparation and use of non-coding RNA (such as ribozymes, rnases P, siRNA, and mirnas) based inhibitory Therapeutics is also known in the art, for example, as described in Sioud, RNA Therapeutics: function, design, AND DELIVERY (Methods in Molecular Biology). Humana Press 2010.
Construction of vectors for expression of polynucleotides useful in the present invention may be accomplished using conventional techniques that do not require detailed explanation to one of ordinary skill in the art. In order to produce an efficient expression vector, it is desirable to have regulatory sequences that control the expression of the polynucleotide. These regulatory sequences include promoter and enhancer sequences and are affected by the particular cytokines with which they interact and are well known in the art.
Gene editing
In some embodiments, the agent that reduces the level and/or activity of BRM/BRG1 is a component of a gene editing system. For example, agents that reduce the level and/or activity of BRM/BRG1 introduce alterations (e.g., insertions, deletions (e.g., knockouts), translocations, inversions, single point mutations, or other mutations) in BRM and/or BRG 1. In some embodiments, the agent that reduces the level and/or activity of BRM/BRG1 is a nuclease. Exemplary gene editing systems include Zinc Finger Nucleases (ZFNs), transcription activator-like effector based nucleases (TALENs), and regularly spaced clustered short palindromic repeats (CRISPR) systems. Methods based on ZFN, TALEN and CRISPR are described, for example, in Gaj et al, trends biotechnol.31 (7): 397-405 (2013).
CRISPR refers to a set of regularly spaced clustered short palindromic repeats (or a system comprising a set of regularly spaced clustered short palindromic repeats). CRISPR systems refer to systems derived from CRISPR and Cas (CRISPR-associated proteins) or other nucleases that can be used to silence or mutate genes described herein. CRISPR systems are naturally occurring systems found in bacterial and archaeal genomes. The CRISPR locus consists of alternating repeat and spacer sequences. In naturally occurring CRISPR systems, the spacer is typically a sequence (e.g., a plasmid or phage sequence) that is foreign to the bacteria. CRISPR systems have been modified for gene editing in eukaryotes (e.g., altering, silencing, and/or enhancing certain genes). See, e.g., WIEDENHEFT et al, nature 482 (7385): 331-338 (2012). For example, such modification of the system includes introducing into eukaryotic cells a plasmid containing a specifically designed CRISPR and one or more appropriate Cas proteins. The CRISPR locus is transcribed into RNA and processed by the Cas protein into a small RNA comprising a repeat sequence flanked by spacers. The RNA serves as a guide for Cas protein silencing of a specific DNA/RNA sequence, depending on the spacer sequence. See, e.g., horvath et al, science 327 (5962): 167-170 (2010); makarova et al, biology Direct 1:7 (2006); pennisi, science341 (6148): 833-836 (2013). In some examples, the CRISPR system comprises a Cas9 protein, a nuclease that cleaves both strands of DNA. See, e.g., id.
In some embodiments, in a CRISPR system for use described herein, e.g., in accordance with one or more methods described herein, the spacer of the CRISPR is derived from a target gene sequence, e.g., from a BRM and/or BRG1 sequence.
In some embodiments, the agent that reduces the level and/or activity of BRM/BRG1 comprises a guide RNA (gRNA) of a CRISPR system for gene editing. Exemplary grnas for use in the methods of the invention are provided in table 1 below. In embodiments, agents that reduce the level and/or activity of BRM and/or BRG1 include ZFNs or mRNA encoding ZFNs that target (e.g., cleave) a nucleic acid sequence (e.g., a DNA sequence) of BRD 7. In embodiments, an agent that reduces the level and/or activity of BRM and/or BRG1 comprises a TALEN or mRNA encoding a TALEN that targets (e.g., cleaves) a nucleic acid sequence (e.g., a DNA sequence) of BRM and/or BRG 1.
For example, gRNA can be used in CRISPR systems to engineer altered genes (e.g., BRM and/or BRG 1). In other examples, ZFNs and/or TALENs can be used to engineer altered genes (e.g., BRMs and/or BRGs 1). Exemplary alterations include insertions, deletions (e.g., knockouts), translocations, inversions, single point mutations, or other mutations. The alteration may be introduced in the gene of the cell, for example in vitro, ex vivo or in vivo. In some embodiments, the alteration reduces (e.g., knocks down or knocks out) the level and/or activity of BRM and/or BRG1, e.g., the alteration is a functional negative regulator. In yet another example, the alteration corrects a defect (e.g., a mutation that results in a defect) in BRM and/or BRG 1.
In certain embodiments, the CRISPR system is used to edit (e.g., add or delete base pairs) a target gene, e.g., BRM and/or BRG1. In other embodiments, CRISPR systems are used to introduce premature stop codons, e.g., to reduce expression of a target gene. In still other embodiments, the CRISPR system is used to reversibly shut down a target gene, e.g., similar to RNA interference. In embodiments, the CRISPR system is used to guide Cas to the promoter of a target gene (e.g., BRM and/or BRG 1), thereby spatially blocking RNA polymerase.
In some embodiments, it may be used, for example, in U.S. publication number 20140068797; cong et al, science 339 (6121): 819-823 (2013); tsai, nature Biotechnol.,32 (6): 569-576 (2014); U.S. patent No. 8,871,445;8,865,406;8,795,965;8,771,945; and 8,697,359 to generate a CRISPR system to edit BRM and/or BRG1.
In some embodiments, CRISPR interference (CRISPRi) techniques can be used for transcriptional repression of specific genes (e.g., genes encoding BRM and/or BRG 1). In CRISPRi, an engineered Cas9 protein (e.g., nuclease-free dCas9 or dCas9 fusion protein, such as dCas9-KRAB or dCas9-SID4X fusion protein) can be paired with a sequence-specific guide RNA (sgRNA). The Cas9-gRNA complex can block RNA polymerase, thereby interfering with transcriptional elongation. The complex may also block transcription initiation by interfering with transcription factor binding. The CRISPRi method is specific, minimal off-target effects, and is multiplexing, e.g., can inhibit more than one gene simultaneously (e.g., using multiple grnas). In addition, the CRISPRi method allows reversible gene suppression. In some embodiments, CRISPR-mediated gene activation (CRISPRa) can be used, for example, for transcriptional activation of one or more genes described herein (e.g., genes that inhibit BRM and/or BRG 1). In CRISPRa technology, dCas9 fusion proteins recruit transcriptional activators. For example, dCas9 can be used to recruit polypeptides (e.g., activation domains), such as VP64 or p65 activation domain (p 65D), and used with sgrnas (e.g., single sgrnas or multiple sgrnas) to activate one or more genes, e.g., endogenous genes. Multiple activating factors can be recruited by using multiple sgrnas-this can increase activation efficiency. Multiple activation domains, single or multiple activation domains, may be used. In addition to engineering dCas9 to recruit activators, sgrnas can also be engineered to recruit activators. For example, RNA aptamers can be incorporated into sgrnas to recruit proteins (e.g., activation domains), such as VP64. In some examples, a co-activation mediator (SAM) system may be used for transcriptional activation. In SAM, MS2 aptamer was added to sgRNA. MS2 recruits MS2 coat protein (MCP) fused to p65AD and heat shock factor 1 (HSF 1). CRISPRi and CRISPRa techniques are described in more detail, for example, in domiiguez et al, nat. Rev. Mol. Cell biol.17 (1): 5-15 (2016), incorporated herein by reference.
Small molecule compounds
In some embodiments of the invention, the agent that decreases the BRM/BRG1 level and/or activity of the cell is a small molecule compound. In some embodiments, the agent that decreases the level and/or activity of BRM/BRG1 has the structure:
other embodiments and exemplary methods for synthetically producing these compounds are described herein.
Medical application
The compounds described herein are useful in the methods of the invention and, while not being bound by theory, are believed to exert their ability to modulate the level, state and/or activity of BAF complexes, i.e., by inhibiting the activity of BRG1 and/or BRM proteins in mammalian BAF complexes. BAF complex-related disorders include, but are not limited to, BRG1 loss-of-function mutation-related disorders.
One aspect of the invention relates to methods of treating a disorder associated with a BRG1 loss of function mutation, such as cancer (e.g., non-small cell lung cancer, colorectal cancer, bladder cancer, primary foci-less tumor, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer), in a subject in need thereof. In some embodiments, the invention relates to methods of treating melanoma (e.g., uveal melanoma), prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer.
In some embodiments, the compound is administered in an amount and for a time effective to result in one or more (e.g., two or more, three or more, four or more) of: (a) a decrease in tumor size, (b) a decrease in tumor growth rate, (c) an increase in tumor cell death, (d) a decrease in tumor progression, (e) a decrease in the number of metastases, (f) a decrease in metastasis rate, (g) a decrease in tumor recurrence, (h) an increase in survival of the subject, and (i) an increase in progression-free survival of the subject.
Treatment of cancer may result in a decrease in the size or volume of the tumor. For example, after treatment, the tumor size is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to the tumor size prior to treatment. The size of the tumor can be measured by any reproducible means of measurement. For example, the size of a tumor can be measured as the diameter of the tumor.
Treatment of cancer may further result in a reduction in the number of tumors. For example, after treatment, the number of tumors is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to the number before treatment. The number of tumors can be measured by any reproducible means of measurement, for example, the number of tumors can be measured by counting tumors that are visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50 x).
Treatment of cancer may result in a reduction in the number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to the number before treatment. The number of transfer nodules may be measured by any reproducible means of measurement. For example, the number of transfer nodules may be measured by counting transfer nodules that are visible to the naked eye or visible at a specified magnification (e.g., 2x, 10x, or 50 x).
Treating cancer may result in an increase in the average survival time of a population of subjects treated according to the invention compared to a population of untreated subjects. For example, the average survival time increases by more than 30 days (more than 60 days, 90 days, or 120 days). The increase in the average survival time of a population can be measured in any reproducible manner. The increase in the average survival time of a population can be measured, for example, by calculating the average length of survival of the population after starting treatment with a compound of the invention. The increase in the average survival time of a population can also be measured, for example, by calculating the average length of survival of the population after completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.
Treatment of cancer may also result in reduced mortality in the treated population of subjects as compared to the untreated population. For example, mortality is reduced by more than 2% (e.g., more than 5%, 10%, or 25%). The reduction in mortality of a population of treated subjects can be measured in any reproducible manner, for example, by calculating the average number of disease-related deaths per unit time after the population has begun to be treated with the pharmaceutically acceptable salts of the invention. The reduction in mortality of a population can also be measured, for example, by calculating the average number of disease-related deaths per unit time of the population after completion of a first round of treatment with the pharmaceutically acceptable salts of the invention.
Exemplary cancers that may be treated by the present invention include, but are not limited to, non-small cell lung cancer, colorectal cancer, bladder cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal gastric cancer, esophageal cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-hodgkin's lymphoma, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancers, thymoma, adrenal cortex cancer, appendiceal cancer, small intestine cancer, hematological cancer, and penile cancer.
Combination preparation and use thereof
The compounds of the invention may be combined with one or more therapeutic agents. In particular, the therapeutic agent may be a therapeutic agent that treats, therapeutically or prophylactically, any of the cancers described herein.
Combination therapy
The compounds of the invention may be used alone or in combination with additional therapeutic agents (e.g., other agents that treat cancer or symptoms associated therewith), or in combination with other types of treatments for cancer. In combination therapy, the dosage of one or more therapeutic compounds may be reduced from the standard dosage when administered alone. For example, the dosages may be determined empirically based on drug combination and alignment, or may be derived by isoradiometric analysis (e.g., black et al, neurology 65: S3-S6, 2005). In this case, the dosage of the compounds should provide a therapeutic effect when combined.
In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in treating cancer). These chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum complexes (platinum coordination complex), anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progestins, estrogens, antiestrogens, androgens, antiandrogens and gonadotropin releasing hormone analogs. Also included are 5-fluorouracil (5-FU), folinic acid (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel and docetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, imperoshu and piposhu; aziridines such as benzotepa (benzodopa), carboquinone (carboquone), metutinib (meturedopa), and uratepa (uredopa); ethyleneimine and methyl melamines, including hexamethylpyrimidine, triethylenemelamine, triethylenephosphoramide (trietylenephosphoramide), triethylenethiophosphamide (triethiylenethiophosphoramide), and trimethylol melamine; annona squamosa lactones (acetogenins) (especially bullatacin and bullatacin ketone (bullatacinone)); camptothecins (including the synthetic analog topotecan); bryozoans; calistatin (callystatin); CC-1065 (including adoxolone, calzelone and bizelone analogues thereof); nostoc (cryptophycin) (in particular, nostoc 1 and nostoc 8); dolastatin; sesqui-carcinomycin (including synthetic analogs, KW-2189 and CB1-TM 1); elstuporin (eleutherobin); a podocarpine (pancratistatin); the stoichiometriol (sarcodictyin); sponge chalone (spongistatin); nitrogen mustards such as chlorambucil, napthalene mustards, chlorophosphamide, estramustine, ifosfamide, dichloromethyldiethylamine, mechlorethamine hydrochloride, melphalan, new enbicine, chlorambucil cholesterol, prednisomustine, triamcinolone, uracil mustards; nitrosoureas such as carmustine, chlorourea, fotemustine, robustadine, nimustine He Leimo statin; antibiotics such as enediynes (e.g., calicheamicin, particularly calicheamicin gamma ll and calicheamicin omega ll (see, e.g., agnew, chem. Intl. Ed Engl. 183-186 (1994)); dactinomycin including dactinomycin A, bisphosphonates such as chlorophosphonates;, epothilones, and neocarcinomycin chromophores and related chromoprotein enediyn antibiotic chromophores), aclacinomycin, actinomycin, amphotericin, diazoserine, bleomycin, actinomycin C, cartrubicin (carabicin), carminomycin, carcinophilin, chromycin (chromomycinis), actinomycin D, daunorubicin, ditetraubicin, 6-diazon-5-oxo-L-norleucine(Doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, exenatide, idarubicin, doxycycline, mitomycin (such as mitomycin C), mycophenolic acid, norgamycin, olivomycin, percomycin, potfiromycin, puromycin, tri-iron doxorubicin, rodubicin, streptozotocin, streptozocin, tubercidin, ubenimex, cilostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as, for example, dimethyl folic acid, methotrexate, pterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thioadenine, thioguanine; pyrimidine analogs such as ambcitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fluorouridine; androgens such as carbosterone, drotasone propionate, cyclothioandrol, emaandran, testosterone; anti-epinephrine such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid (frolinic acid); acetoglucurolactone; aldehyde phosphoramidate glycoside (aldophosphamide glycoside); aminolevulinic acid; enuracil; amsacrine; bei Sibu west (bestrabucil); a specific group; eda traxas; ground phosphoramide (defofamine); dimecoxin (demecolcine); deaquinone; elfomithine; ammonium elegance (elliptinium acetate); epothilones; an ethyleneoxy pyridine; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids (maytansinoids) such as maytansine and ansamitocins; propamidine hydrazone; mitoxantrone; mo Pai darol (mopidanmol); nylon Qu Ading; prastatin; egg ammonia nitrogen mustard; pirarubicin; losoxantrone; podophylloic acid; 2-ethyl hydrazine; procarbazine; /(I)Polysaccharide complex (JHS Natural Products, eugene, oreg.); carrying out a process of preparing the raw materials; rhizopus extract; dorzolopyran (sizofuran); spiral germanium; tenuazonic acid; triiminoquinone; 2,2',2 "-trichloroethylamine; trichothecene toxins (particularly T-2 toxin, wart A (verracurin A), cyclosporin a, and serpentine; uratam; vindesine; azazolamide; mannosamine; dibromomannitol; dibromodulcitol; pipobromine; ganciclovir (gacytosine); arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, e.g./>Paclitaxel (Bristol-Myers Squibb Oncology, prencton, N.J.),/>Albumin engineered nanoparticle formulations of paclitaxel without cremophor (American Pharmaceutical Partners, schaumberg, ill.) and/>Docetaxel (Rhone-Poulenc Rorer, antony, france); chlorambucil; Gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; /(I) Vinorelbine; nux An Tuo; teniposide; eda traxas; daunorubicin; aminopterin; hilded; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS2000; difluoromethyl ornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents may be used in a mixture for administration in combination with a first therapeutic agent as described herein. Suitable dosing regimens for combination chemotherapy are known in the art and are described, for example, in Saltz et al (1999) Proc ASCO 18:233a and Douillard et al (2000) Lancet 355:1041-7.
In some embodiments, the second therapeutic agent is a therapeutic agent for a biologic such as a cytokine (e.g., an interferon or an interleukin (e.g., IL-2)) for the treatment of cancer. In some embodiments, the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumabIn some embodiments, the biological agent is an immunoglobulin-based biological agent, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof), that agonizes the target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer. Such agents include Rituxan (rituximab); cenipenem (daclizumab); simulect (basiliximab); synagis (palivizumab); class g (infliximab); herceptin (trastuzumab); wheat-head (gemtuzumab ozogamicin); canpase (alemtuzumab); zerewalin (tiuxetan); salmeterol (adalimumab); sorel (omalizumab); heck sand (tositumomab-I-131); raptiva (efacient); erbitux (cetuximab); avastin (bevacizumab); tysabri (natalizumab); yamero (tolizumab); vitamin bixafen (panitumumab); norubicin (ranibizumab); shu Lirui (eculizumab); simendan (pezilizumab); euphorbia (golimumab); ilaris (kanamazumab); hiddano (Wu Sinu mab); arzerra (aframomumab); pr Luo Li (Deshu mab); numax (mevinizumab); ABThrax (Lei Xiku mab); doubly Libang (belieukinumab); yervoy (ipilimumab); adcetris (bentuximab); panett (pertuzumab); herly (trastuzumab maytansinoid conjugate); and rituximab (otophyllizumab). Antibody-drug conjugates are also included.
The second agent may be a therapeutic agent that is not a drug treatment. For example, the second therapeutic agent is radiation therapy, cryotherapy, thermotherapy, and/or surgical excision of tumor tissue.
The second agent may be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). Antibodies may be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (e.g., an inhibitory antibody or small molecule inhibitor) (e.g., an anti-CTLA 4 antibody such as ipilimumab/yervey or tremelimumab). In some embodiments, the checkpoint inhibitor is an inhibitor of PD-1 (e.g., an inhibitory antibody or small molecule inhibitor) (e.g., nivolumab +.Palbociclib/tPittuzumab/CT-011). In some embodiments, the checkpoint inhibitor is an inhibitor of PD-L1 (e.g., an inhibitory antibody or small molecule inhibitor) (e.g., MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559). In some embodiments, the checkpoint inhibitor is an inhibitor of PDL2 (e.g., an inhibitory antibody or Fc fusion protein or small molecule inhibitor) (e.g., a PDL2/Ig fusion protein, such as AMP 224). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA 271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, or a combination thereof.
In some embodiments, the compounds of the invention are used in combination with another anti-cancer therapy (such as surgery, a MEK inhibitor and/or a PKC inhibitor, or a combination thereof) for the treatment of uveal melanoma. For example, in some embodiments, the methods further comprise performing a surgical procedure before, after, or simultaneously with the administration of the compounds of the invention. In some embodiments, the methods further comprise administering a MEK inhibitor (e.g., semanteme, bimatinib, or trimetinib) and/or a PKC inhibitor (e.g., cable Qu Tuolin or IDE 196) before, after, or simultaneously with administration of a compound of the invention.
In any of the combination embodiments described herein, the first therapeutic agent and the second therapeutic agent are administered simultaneously or sequentially in either order. The first therapeutic agent may be administered immediately before or after the second therapeutic agent for up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7, 1-14, 1-21, or 1-30 days.
Pharmaceutical composition
The compounds of the invention are preferably formulated as pharmaceutical compositions in a biocompatible form suitable for in vivo administration for administration to a mammal, preferably a human. Accordingly, in one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention in admixture with a suitable diluent, carrier or excipient.
The compounds of the present invention may be used in the form of the free base, in the form of salts, solvates and as prodrugs. All forms are within the scope of the invention. According to the methods of the present invention, the compounds, or salts, solvates, or prodrugs thereof, may be administered to a patient in a variety of forms depending on the route of administration selected, as will be appreciated by those skilled in the art. The compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration, and the pharmaceutical compositions may be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transdermal, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.
The compound of the invention may be administered orally, for example with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be mixed directly with the food in the diet. For oral therapeutic administration, the compounds of the present invention may be mixed with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups and wafers (wafer).
The compounds of the invention may also be administered parenterally. Solutions of the compounds of the present invention may be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersants may also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohols, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington, pharmaceutical Sciences (2003, 20 th edition) and The United States Pharmacopeia: the National Formulary (USP 24NF 19), 1999 publications. Pharmaceutical dosage forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that easy administration by syringe is possible.
The compounds described herein may be administered intratumorally, for example as an intratumoral injection. Intratumoral injection is direct injection into the tumor vasculature, particularly contemplated for discrete, solid, accessible tumors. Local, regional or systemic administration may also be appropriate. The compounds described herein may advantageously be contacted by administering one or more injections (e.g., spaced at about 1cm intervals) to the tumor. In the case of surgical interventions, the invention may be used preoperatively, such as to allow inoperable tumors to undergo resection. Continuous administration may also be applied where appropriate, for example by implantation of a catheter into a tumor or into the tumor vasculature.
The compounds of the invention may be administered to an animal (e.g., a human) alone or in combination with a pharmaceutically acceptable carrier, as described herein, in proportions determined by the solubility and chemical nature of the compound, the route of administration selected, and standard pharmaceutical practice.
Dosage of
The dosage of the compounds of the invention and/or compositions comprising the compounds of the invention may vary depending on a number of factors, such as the pharmacodynamic properties of the compounds; the mode of administration; age, health, and weight of the recipient; the nature and extent of the symptoms; frequency of treatment and type of concurrent treatment (if any); and clearance of the compound in the animal to be treated. The appropriate dosage can be determined by one skilled in the art based on the factors described above. The compounds of the invention may be administered initially in a suitable dosage which may be adjusted as required by the clinical response. In general, satisfactory results are obtained when the compounds of the invention are administered to a human in daily doses, for example between 0.05mg and 3000mg (measured in solid form). Alternatively, the weight of the patient may be used to calculate the dose. For example, the dosage of the compound or pharmaceutical composition thereof administered to the patient ranges from 0.1 to 50mg/kg.
In some embodiments, the dose of the compound, agent, or pharmaceutical composition thereof (e.g., compound 1) may be between 1mg and 15mg (e.g., about 1mg to 2.5mg, about 2.5mg to 5mg, about 5mg to 7.5mg, or about 7.5mg to about 10 mg). In some embodiments, the dose of the compound, agent, or pharmaceutical composition thereof (e.g., compound 1) is about 2mg to 3mg (e.g., about 2.5 mg). In some embodiments, the dose of the compound, agent, or pharmaceutical composition thereof (e.g., compound 1) is about 4mg to 6mg (e.g., about 5 mg). In some embodiments, the dose of the compound, agent, or pharmaceutical composition thereof (e.g., compound 1) is about 7mg to 8mg (e.g., about 7.5 mg). In some embodiments, the dose of the compound, agent, or pharmaceutical composition thereof (e.g., compound 1) is about 9mg to 11mg (e.g., about 10 mg).
In some embodiments, the compound, agent, or pharmaceutical composition thereof (e.g., compound 1) is administered in more than one dose, and these doses are administered once daily, twice daily (BID), once weekly, once every two weeks, or once monthly. In some embodiments, administration comprises multiple doses that are at least 7 days in duration, e.g., at least 7 days, 8 days, 9 days, 10 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, or longer.
In some embodiments, the compound, agent, or pharmaceutical composition thereof (e.g., compound 1) is administered once daily for one week, is deactivated for one week, and is administered for one or more cycles. In some embodiments, a compound, agent, or pharmaceutical composition thereof (e.g., compound 1) is administered at a dose described herein (e.g., a dose of about 2.5mg, 5mg, 7.5mg, or 10 mg) once daily for one week, and is discontinued for one week for one or more cycles.
In some embodiments, the compound, agent, or pharmaceutical composition thereof (e.g., compound 1) is administered once daily for two weeks, is deactivated for one week, and is administered for one or more cycles. In some embodiments, a compound, agent, or pharmaceutical composition thereof (e.g., compound 1) is administered at a dose described herein (e.g., a dose of about 2.5mg, 5mg, 7.5mg, or 10 mg) once daily for two weeks, and is discontinued for one week for one or more cycles.
Examples
The following abbreviations are used throughout the examples section.
Boc t-Butoxycarbonyl group
DCM dichloromethane
DIPEA or DIEA n, n-diisopropylethylamine
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
EDCI N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride
EEDQ 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline
EtOH ethanol
H or hr hours
HOBt or HOBT 1-hydroxybenzotriazole hydrate
MeOH methanol
MsCl methanesulfonyl chloride
NaHMDS sodium bis (trimethylsilyl) amide
PdCl 2 (dtbpf) [1,1' -bis (di-tert-butylphosphino) ferrocene ] dichloropalladium (II)
THF tetrahydrofuran
TMSCHN 2 (diazomethyl) trisilane
Example 1 preparation of N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide
As shown in scheme 1 below, N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide was synthesized.
Scheme 1.
Step 1: preparation of 6-fluoropyridine-2-carbonyl chloride (intermediate B)
To a cooled (0 ℃) solution of 6-fluoropyridine-2-carboxylic acid (50.0 g,354 mmol) in dichloromethane (500 mL) and N, N-dimethylformamide (0.26 mL,3.54 mmol) was added oxalyl chloride (155 mL,1.77 mol). After the oxalyl chloride addition was complete, the reaction mixture was warmed to room temperature. After 0.5h, the mixture was concentrated in vacuo to afford intermediate B (56.50 g) as a white solid, which was used in the next step without further purification.
Step 2: preparation of 2-chloro-1- (6-fluoro-2-pyridinyl) ketene (intermediate C)
To a cooled (0 ℃) mixture of intermediate B (56.0 g,351 mmol) in 1, 4-dioxane (800 mL) was added a solution of 2M trimethylsilyl diazomethane in hexane (351 mL,702 mmol) in a dropwise manner. The resulting reaction mixture was stirred at 25℃for 10h. The reaction mixture was then quenched with a solution of 4M HCl in 1, 4-dioxane (500 ml,2.0 mol). After stirring for 2h, the reaction solution was concentrated in vacuo to give an oil. The residue was diluted with saturated aqueous NaHCO 3 and extracted three times with ethyl acetate. The combined organic layers were washed twice with brine, dried over Na 2SO4, filtered and concentrated under reduced pressure to give intermediate C (35.5 g) as a white solid, which was used directly in the next step.
LCMS(ESI)m/z:[M+H]+=173.8。
Step 3: preparation of 4- (6-fluoro-2-pyridinyl) thiazol-2-amine (intermediate E)
To a solution of intermediate C (35.5 g,205 mmol) and thiourea (14.0 g,184 mmol) in a mixture of methanol (250 mL) and water (250 mL) was added NaF (3.56 g,84.8 mmol) at room temperature. After stirring for 0.5h, the reaction mixture was concentrated in partial vacuum to remove MeOH, and the resulting solution was acidified to pH about 3 with 2M aqueous HCl. After 15 minutes, the solution was extracted three times with ethyl acetate. The organic layer was discarded, the aqueous phase was basified with saturated aqueous NaHCO 3, stirred for 30 min and extracted three times with ethyl acetate. The combined organic layers were washed three times with brine, dried over Na 2SO4, filtered and concentrated under reduced pressure. The residue was triturated with petroleum ether, stirred for 10 minutes at 25 ℃ and filtered. The resulting solid was dried in vacuo to afford intermediate E (28.0 g,143mmol,70.1% yield, 100% purity) as a white solid.
LCMS(ESI)m/z:[M+H]+=195.8。
1H NMR(400MHz,DMSO-d6)δ8.00-7.96(m,1H),7.72(d,J=7.2Hz,1H),7.24(s,1H),7.16(s,2H),7.02(d,J=8.0Hz,1H).
Step 4: preparation of 4- [6- [ cis-2, 6-dimethylmorpholin-4-yl ] -2-pyridinyl ] thiazol-2-amine (intermediate G)
Ten separate mixtures of intermediate E (2.00 g,10.3 mmol), cis-2, 6-dimethylmorpholine (3.54 g,30.7 mmol) and DIPEA (5.35 mL,30.7 mmol) in dimethyl sulfoxide (10 mL) were stirred in parallel at 120 ℃ under an atmosphere of N 2. After 36h, the reaction mixtures were combined and added dropwise to water. The resulting suspension was filtered, the filter cake was washed three times with water and once with petroleum ether, then dried under reduced pressure to give intermediate G (25.5G, 87.8mmol,95.2% yield) as a yellow solid.
LCMS(ESI)m/z:[M+H]+=291.2。
1H NMR(400MHz,DMSO-d6)δ7.56-7.54(m,1H),7.17(s,1H),7.13(d,J=7.6Hz,1H),7.01(s,2H),6.72(d,J=8.8Hz,1H),4.26-4.15(m,2H),3.67-3.55(m,2H),2.38-2.34(m,2H),1.17(d,J=6.4Hz,6H).
Step 5: preparation of tert-butyl N- [ (1S) -2- [ [4- [6- [ cis-2, 6-dimethylmorpholin-4-yl ] -2-pyridinyl ] thiazol-2-yl ] amino ] -1- (methoxymethyl) -2-oxo-ethyl ] carbamate (intermediate I)
To a solution of intermediate G (12.0G, 41.3 mmol) and (2S) -2- (tert-butoxycarbonylamino) -3-methoxy-propionic acid (10.9G, 49.6 mmol) in dichloromethane (60 mL) was added EEDQ (12.3G, 49.6 mmol). After stirring at room temperature for 16h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1 to 3:2) to give intermediate I (20.0 g,40.7mmol,98.5% yield) as a yellow gum.
LCMS(ESI)m/z:[M+H]+=492.2。
1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),7.78(s,1H),7.64-7.60(m,1H),7.25(d,J=7.2Hz,1H),7.16(d,J=7.2Hz,1H),6.79(d,J=8.4Hz,1H),4.50-4.48(m,1H),4.25(d,J=11.6Hz,2H),3.70-3.51(m,4H),3.26(s,3H),2.44-2.40(m,2H),1.39(s,9H),1.18(d,J=6.4Hz,6H).
Step 6: preparation of (S) -4- (4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) -1-methoxy-3-oxobutane-2-ammonium chloride (intermediate J)
To a solution of 4M HCl in 1, 4-dioxane (200 mL,800 mmol) was added a solution of intermediate I (20.0 g,40.7 mmol) in dichloromethane (50 mL). After stirring at room temperature for 2h, the mixture was diluted with methyl tert-butyl ether to give a suspension. The solid was collected by filtration, washed twice with methyl tert-butyl ether, and dried in vacuo to give intermediate J (19.0 g) as a yellow solid, which was used in the next step without further purification.
LCMS(ESI)m/z:[M+H]+=392.3。
1H NMR(400MHz,DMSO-d6)δ13.44-12.30(m,1H),8.65(d,J=4.4Hz,3H),7.87(s,1H),7.66-7.64(m,1H),7.25(d,J=7.2Hz,1H),6.83(d,J=8.8Hz,1H),4.39-4.30(m,1H),4.25(d,J=11.6Hz,2H),3.94-3.86(m,1H),3.85-3.77(m,1H),3.69-3.57(m,2H),3.31(s,3H),2.43(m,2H),1.18(d,J=6.4Hz,6H).
Preparation of 1- (methylsulfonyl) -1H-pyrrole-3-carboxylic acid (intermediate K)
As shown in scheme 2 below, 1- (methylsulfonyl) -1H-pyrrole-3-carboxylic acid was synthesized.
Scheme 2
Step A: preparation of tert-butyl 1H-pyrrole-3-carboxylate (intermediate N)
To a mixture of tert-butyl-prop-2-enoate (78.6 mL, 552 mmol) and 1- (isocyanomethylsulfonyl) -4-methylbenzene (106 g, 552 mmol) in THF (1300 mL) at 30℃over 1 hour was slowly added 60% NaH in mineral oil (25.97 g,649 mmol) and then heated to 70 ℃. After 2h, the reaction mixture was poured into saturated aqueous NH 4 Cl and extracted three times with ethyl acetate. The combined organic phases were washed twice with brine, dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1 to 3:1) to give intermediate N (41.5 g,236mmol,43% yield) as a yellow solid.
LCMS(ESI)m/z[M+Na]+=180.4。
1H NMR(400MHz,CDCl3)δ8.36(br s,1H),7.35-7.25(m,1H),6.71-6.62(m,1H),6.59-6.49(m,1H),1.48(s,9H).
And (B) step (B): preparation of 1-methylsulfonylpyrrole-3-carboxylic acid tert-butyl ester (intermediate O)
To a cooled solution (0 ℃) of intermediate N (40.5 g,242 mmol) in THF (1500 mL) was added a 1M solution of NaHMDS (284 mL, 284 mmol). After stirring at 0deg.C for 30min, methanesulfonyl chloride (28.1 mL, 803 mmol) was slowly added and the mixture was warmed to 30deg.C. After 16h, the reaction mixture was slowly poured into saturated aqueous NH 4 Cl and extracted three times with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=10:1) to give a yellow solid. The yellow solid was triturated with methyl tert-butyl ether at room temperature, stirred for 20 minutes, filtered, and dried in vacuo to give intermediate O (25.7 g,105mmol,43% yield) as a white solid.
1H NMR(400MHz,CDCl3)δ7.66-7.64(m,1H),7.10-7.08(m,1H),6.73-6.71(m,1H),3.21(s,3H),1.56(s,9H).
Step C: preparation of 1-methylsulfonylpyrrole-3-carboxylic acid (intermediate K)
To a mixture of intermediate O (25.7 g,105 mmol) in 1, 4-dioxane (100 mL) was added a 4M solution of HCl in 1, 4-dioxane (400 mL,1.6 mol) at 15 ℃. After stirring at 15 ℃ for 14h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with methyl tert-butyl ether at 15℃for 16h. The mixture was filtered and dried in vacuo to give intermediate K (18.7 g,98.8mmol,94% yield) as a white solid.
LCMS(ESI)m/z[M+H]+=189.8。
1 H NMR (400 MHz, methanol-d 4) delta 7.78-7.77 (m, 1H), 7.25-7.23 (m, 1H), 6.72-6.70 (m, 1H), 3.37 (s, 3H).
Step 7: preparation of N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide
To a solution of 1-methylsulfonylpyrrole-3-carboxylic acid (intermediate K) (2.43 g,12.9 mmol), EDCI (2.69 g,14.0 mmol), HOBt (1.89 g,14.0 mmol) and DIPEA (10.2 mL,58.4 mmol) in dichloromethane (50 mL) was added intermediate J (5.00 g,11.7 mmol). After stirring at room temperature for 4h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed three times with saturated aqueous NH 4 Cl, once with brine, dried over Na 2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1 to 1:2). The residue was triturated with methyl tert-butyl ether. After 0.5h, the suspension was filtered, the filter cake was washed with methyl tert-butyl ether and dried in vacuo. The solid was dissolved in dimethylsulfoxide (12 mL) and added drop-wise to water (800 mL). The suspension was filtered to give a wet cake. The filter cake was suspended in water and stirred at room temperature. After 1 hour, the solid was collected by filtration, washed three times with water and dried in vacuo to give N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide (3.9 g,6.93mmol,59.3% yield) as a white solid.
LCMS(ESI)m/z:[M+H]+=563.1。
1H NMR(400MHz,DMSO-d6)δ12.49(br s,1H),8.51(d,J=7.2Hz,1H),7.98-7.97(m,1H),7.78(s,1H),7.67-7.57(m,1H),7.29-7.27(m,1H),7.26(d,J=7.2Hz,1H),6.88-6.74(m,2H),4.94-4.91(m,1H),4.25(d,J=11.6Hz,2H),3.77-3.67(m,2H),3.63-3.62(m,2H),3.57(s,3H),3.31(s,3H),2.44-2.38(m,2H),1.18(d,J=6.0Hz,6H).
EXAMPLE 2 preparation of N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3- (methoxy-d 3) -1-oxopropan-2-yl-3, 3-d 2) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide
The synthetic scheme described in example 1 was followed to prepare N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3- (methoxy-d 3) -1-oxopropan-2-yl-3, 3-d 2) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide wherein intermediate H was replaced with N- (tert-butoxycarbonyl) -O- (methyl-d 3) -L-serine-3, 3-d 2. N- (tert-Butoxycarbonyl) -O- (methyl-d 3) -L-serine-3, 3-d 2 was prepared from isotopically enriched materials according to the synthetic procedure described in A.Yang et al, org.Process Res. Dev.2019, 23, 818-824.
LCMS(ESI)m/z:[M+H]+=568.2。
1H NMR(400MHz,DMSO-d6)δ12.45(s,1H),8.47(d,J=7.2Hz,1H),7.98(dd,J=2.3,1.7Hz,1H),7.78(s,1H),7.62(dd,J=8.5,7.4Hz,1H),7.29(dd,J=3.2,2.3Hz,1H),7.26(d,J=7.3Hz,1H),6.84–6.75(m,2H),4.91(d,J=7.2Hz,1H),4.25(dd,J=13.1,2.3Hz,2H),3.69–3.59(m,2H),3.56(s,3H),2.42(dd,J=12.8,10.5Hz,2H),1.18(d,J=6.2Hz,6H).
Example 3 preparation of N- ((R) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3- (methoxy) -1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide
N- ((R) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3- (methoxy) -1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide was prepared according to the synthetic scheme described in example 1, wherein intermediate H was replaced by (2R) -2- (tert-butoxycarbonylamino) -3-methoxy-propionic acid.
LCMS(ESI)m/z:[M+H]+=563.1。
1H NMR(400MHz,DMSO-d6)δ12.5(s,1H),8.50(d,J=7.2Hz,1H),7.98(t,J=1.6Hz,1H),7.78(s,1H),7.62(dd,J=7.2,8.4Hz,1H),7.29(dd,J=2.0,3.2Hz,1H),7.26(d,J=7.2Hz,1H),6.79-6.81(m,2H),4.92(q,J=6.4,12.8Hz,1H),4.25(d,J=11.2Hz,2H),3.69-3.75(m,2H),3.59-3.66(m,2H),3.56(s,3H),3.31(s,3H),2.41(dd,J=10.8,12.8Hz,2H),1.18(d,J=6.0Hz,6H).
EXAMPLE 4 preparation of N- ((R) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3- (methoxy-d 3) -1-oxopropan-2-yl-3, 3-d 2) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide
The synthetic scheme described in example 1 was followed to prepare N- ((R) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3- (methoxy-D 3) -1-oxopropan-2-yl-3, 3-D 2) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide wherein intermediate H was replaced with N- (tert-butoxycarbonyl) -O- (methyl-D 3) -D-serine-3, 3-D 2. N- (tert-Butoxycarbonyl) -O- (methyl-D 3) -D-serine-3, 3-D 2 was prepared from isotopically enriched materials according to the synthetic procedure described in A.Yang et al, org. Process Res. Dev.2019, 23, 818-824.
LCMS(ESI)m/z:[M+H]+=568.3。
1H NMR(400MHz,DMSO-d6)δ12.46(s,1H),8.52–8.38(m,1H),7.97(t,J=1.9Hz,1H),7.76(s,1H),7.62(dd,J=8.5,7.3Hz,1H),7.29(dd,J=3.3,2.3Hz,1H),7.26(d,J=7.4Hz,1H),6.79(dt,J=5.1,1.8Hz,2H),4.89(d,J=5.2Hz,1H),4.31–4.20(m,2H),3.63(ddd,J=10.5,6.2,2.5Hz,2H),3.56(s,3H),2.41(dd,J=12.8,10.5Hz,2H),1.18(d,J=6.2Hz,6H).
Example 5 determination of ATPase catalytic Activity of BRM and BRG-1
ATPase catalytic activity of BRM or BRG-1 is measured by an in vitro biochemical assay using ADP-Glo TM (Promega, V9102). Once the reaction is complete, the ADP-Glo TM kinase assay is performed in two steps. The first step is to deplete any unconsumed ATP in the reaction. The second step is to convert the reaction product ADP to ATP, which the luciferase will use to produce luminescence, and which is detected by a luminescence reader (such as Envision).
Assay reaction mixtures (10. Mu.L) contained 30nM BRM or BRG-1, 20nM salmon sperm DNA (from Invitrogen, ultraPure TM salmon sperm DNA solution, catalog No. 15632011) and 400. Mu.M ATP in ATPase assay buffer containing 20mM Tris, pH 8, 20mM MgCl 2, 50mM NaCl,0.1%Tween-20 and 1mM fresh DTT (Pierce TM DTT (dithiothreitol), catalog No. 20290). The reaction was started by adding 2.5. Mu.L of ATPase solution to 2.5. Mu.L of ATP/DNA solution on a low volume white Proxiplate-384plus plate (Perkinelmer, cat. 6008280) and incubating the reaction at room temperature for 1 hour. Then, the reaction was incubated at room temperature for 40 minutes, followed by addition of 5. Mu.L of ADP-Glo TM reagent provided in the kit. Then 10 μl of kinase detection reagent provided in the kit was added to convert ADP to ATP and the reaction was incubated for 60 minutes at room temperature. Finally, luminescence measurements are collected with a plate reader photometer (such as Envision).
BRM and BRG-1 are synthesized by High Five insect cell lines with purity greater than 90%.
N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide was found in the assay to be 3.9nM and 5.2nM for BRM and IP 50 for BRG1, respectively. N- ((R) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3- (methoxy-d 3) -1-oxopropan-2-yl-3, 3-d 2) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide was found to have an IP 50 of 443nM and 777nM for BRM and for BRG1 in the assay. In the assay N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3- (methoxy-d 3) -1-oxopropan-2-yl-3, 3-d 2) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide was found to be 4.6nM and 7.4nM for BRM and for IP 50 of BRG1, respectively.
EXAMPLE 6 Synthesis of Compound A
BRG1/BRM inhibitor compound a has the following structure:
Compound a was synthesized as shown in scheme 3 below.
Scheme 3 Synthesis of Compound A
ATPase catalytic activity of BRM or BRG-1 in the presence of Compound A was measured by an in vitro biochemical assay using ADP-Glo TM (Promega, V9102) as described above. Compound a was found to have IP 50 for BRM and BRG1 of 10.4nM and 19.3nM, respectively, in the assay.
Example 7 effect of BRG1/BRM ATPase inhibition on the growth of uveal melanoma and hematological cancer cell lines
The procedure is as follows: the uveal melanoma cell line (92-1, MP41, MP38, MP 46), prostate cancer cell Line (LNCAP), lung cancer cell line (NCI-H1299) and immortalized embryonic kidney cell line (HEK 293T) were plated into 96-well plates with growth medium (see table 1). BRG1/BRM ATPase inhibitor compound A is dissolved in DMSO and added to the cells at the time of plating at a concentration gradient of 0 to 10. Mu.M. Cells were incubated at 37℃for 3 days. Three days after treatment, the medium was removed from the cells and 30 microliters of TrypLE (Gibco) was added to the cells for 10 minutes. Cells were separated from the plates and resuspended by adding 170 microliters of growth medium. Cells from two DMSO-treated control wells were counted and the initial cell number plated at the start of the experiment was re-plated into plates containing fresh compound for another four days at 37 ℃. On day 7, cells were harvested as described above. On days 3 and 7, relative Cell growth was measured by adding Cell-titer glo (Promega) and luminescence was measured on an Envision plate reader (PERKIN ELMER). Compound concentrations were calculated using GRAPHPAD PRISM at 50% inhibition of growth (GI 50) for each cell line and plotted as follows. The above method was performed with the following modifications for multiple myeloma cell lines (OPM 2, MM1S, LP 1), ALL cell lines (TALL 1, JURKAT, RS 411), DLBCL cell lines (sudal 6, sudal 4, DB, WSUDLCL2, PFEIFFER), AML cell line (OCIAML), MDS cell line (SKM 1), ovarian cancer cell line (OV 7, TYKNU), esophageal cancer cell line (KYSE 150), rhabdoid tumor cell line (RD, G402, G401, HS729, a 204), liver cancer cell line (HLF, HLE, PLCRPF 5) and lung cancer cell line (SW 1573, NCIH 2444): cells were plated into 96-well plates and on the next day BRG1/BRM atpase inhibitor compound a was dissolved in DMSO and added to cells at a concentration gradient of 0 to 10 μm. At day 3 and day 7 cell divisions, cells were divided into new 96-well plates and fresh compound was added four hours after re-plating. Table 1 lists the cell lines tested and the growth media used.
TABLE 1 cell lines and growth media
Cell lines | Source(s) | Growth medium |
92-1 | SIGMA | RPMI1640+20%FBS |
A204 | ATCC | McCoy′s 5A+10%FBS |
DB | ATCC | RPMI1640+10%FBS |
G401 | ATCC | McCoy′s 5A+10%FBS |
G402 | ATCC | McCoy′s 5A+10%FBS |
HEK293T | ATCC | DMEM+10%FBS |
HLE | JCRB | DMEM+10%FBS |
HLF | JCRB | DMEM+10%FBS |
HS729 | ATCC | DMEM+10%FBS |
JURKAT | ATCC | RPMI1640+10%FBS |
KYSE150 | DSMZ | RPMI1640/Ham′s F12+10%FBs |
LNCAP | ATCC | RPMI1640+10%FBS |
LP1 | DSMZ | IMDM+20%FBS |
MM1S | ATCC | RPMI1640+10%FBS |
MP38 | ATCC | RPMI1640+20%FBS |
MP41 | ATCC | RPMI1640+20%FBS |
MP46 | ATCC | RPMI1640+20%FBS |
NCIH1299 | ATCC | RPMI1640+1D%FBS |
NCIH2444 | ATCC | RPMI1640+20%FBS |
OCIAML5 | DSMZ | α-MEM+20%FBS+10ng/ml GM-CSF |
OPM2 | DSMZ | RPMI1640+10%FBS |
OV7 | ECACC | DMEM/Ham's F12 (1:1) +2mM glutamine+10% FBS+0.5ug/m hydrocortisone+10 ug/ml insulin |
PFEIFFER | ATCC | RPMI1640+10%FBS |
PLCPRF5 | ATCC | EMEM+10%FBS |
RD | ATCC | DMEM+10%FBS |
RS411 | ATCC | RPMI1640+10%FBS |
SKM1 | JCRB | RPMI1640+10%FBS |
SUDHL4 | DSMZ | RPMI1640+10%FBS |
SUDHL6 | ATCC | RPMI1640+20%FBS |
SW1573 | ATCC | DMEM+10%FBS |
TALL1 | JCRB | RPMI1640+10%FBS |
TYKNU | JCRB | EMEM+20%FBS |
WSUDLCL2 | DSMZ | RPMI1640+10%FBS |
Results: as shown in fig. 1, uveal melanoma and hematological cancer cell lines were more sensitive to BRG1/BRM inhibition than the other cell lines tested. Inhibition of uveal melanoma and hematological cancer cell lines was maintained until day 7.
Example 8 comparison of BRG1/BRM inhibitor with clinical PKC and MEK inhibitors in uveal melanoma cell lines
The procedure is as follows: the uveal melanoma cell line 92-1 or MP41 was plated into 96-well plates in the presence of growth medium (see Table 1). BAF atpase inhibitors (compound a), PKC inhibitors (LXS 196; medChemExpress) or MEK inhibitors (semitinib; SELLECK CHEMICALS) were dissolved in DMSO and added to cells at the time of plating in a concentration gradient of 0 to 10 μm. Cells were incubated at 37℃for 3 days. Three days after treatment, cell growth was measured with Cell-titer glow (Promega) and luminescence read on an Envision plate reader (PERKIN ELMER).
Results: as shown in fig. 2 and 3, compound a showed comparable growth inhibition of uveal melanoma cells as clinical PKC and MEK inhibitors. Furthermore, compound a was found to inhibit more rapidly than clinical PKC and MEK inhibitors.
EXAMPLE 9 Synthesis of Compound B
BRG1/BRM inhibitor compound B has the following structure:
Compound B was synthesized as shown in scheme 4 below.
Scheme 4 Synthesis of Compound B
To a mixture of (2S) -2-amino-4-methylsulfanyl-N- [4- [3- (4-pyridinyl) phenyl ] thiazol-2-yl ] butanamide (2 g,4.75mmol, HCl salt) and 1-methylsulfonylpyrrole-3-carboxylic acid (898.81 mg,4.75 mmol) in DMF (20 mL) was added EDCI (1.37 g,7.13 mmol), HOBt (962.92 mg,7.13 mmol) and DIEA (2.46 g,19.00mmol,3.31 mL) and the mixture was stirred at 25℃for 3h. The mixture was poured into H 2 O (100 mL) and the precipitate was collected by filtration. The solid was triturated in MeOH (20 mL) and the precipitate collected by filtration. The solid was dissolved in DMSO (10 mL), then the mixture was poured into MeOH (50 mL), the precipitate formed was collected by filtration and lyophilized to give compound B as a white solid (2.05 g,3.66mmol,77.01% yield).
LCMS(ESI)m/z[M+H]+=555.9。
1H NMR(400MHz,DMSO)δ12.49(s,1H),8.68-8.66(m,2H),8.46(d,J=7.2Hz,1H),8.31-8.30(m,1H),8.02-8.00(m,1H),7.94-7.96(m,1H),7.83(s,1H),7.73-7.74(m,3H),7.61-7.57(m,1H),7.31-7.29(m,1H),6.79-6.77(m,1H),4.74-4.69(m,1H),3.57(s,3H),2.67-2.53(m,2H),2.13-2.01(m,5H).ee%=100%.
Compound B was found to have IP 50 for BRM and BRG1 of 3.6nM and 5.7nM, respectively, in the atpase assay.
Example 10 effect of BRG1/BRM ATPase inhibition on uveal melanoma, hematological cancer, prostate cancer, breast cancer, and Ewing sarcoma cell line growth
The procedure is as follows: as described above, all cell lines described in example 7 above were also tested with compound B. In addition, the following cell lines were also tested as follows. Briefly, the above method was modified for ewing's sarcoma cell line (CADOES, RDES, SKES 1), retinoblastoma cell line (WERIRB), ALL cell line (REH), AML cell line (KASUMI 1), prostate cancer cell line (PC 3, DU145, 22RV 1), melanoma cell line (SH 4, SKMEL28, WM115, COLO829, SKMEL3, a 375), breast cancer cell line (MDAMB 415, CAMA1, MCF7, BT474, HCC1419, DU4475, BT 549), B-ALL cell line (SUPB), CML cell line (K562, MEG 01), burkitt lymphoma cell line (RAMOS 2G64C10, DAUDI), mantle cell lymphoma cell line (JEKO 1, REC 1), bladder cancer cell line (HT 1197) and lung cancer cell line (SBC 5): cells were plated in 96-well plates and on the next day BRG1/BRM atpase inhibitor compound B was dissolved in DMSO and added to cells at a concentration gradient of 0 to 10 μm. At day 3 and day 7 cell divisions, cells were divided into new 96-well plates and fresh compound was added four hours after re-plating. Table 2 lists the cell lines tested and the growth media used.
TABLE 2 cell lines and growth media
Cell lines | Source(s) | Growth medium |
22RV1 | ATCC | RPMI1640+10%FBS |
A375 | ATCC | DMEM+10%FBS |
BT474 | ATCC | Hybricare Medium+1.5 g/L sodium bicarbonate+10% FRS |
BT549 | ATCC | RPMI1640+0.023IU/ml insulin+10% FBs |
CADOES1 | DSMZ | RPMI1640+10%FBS |
CAMA1 | ATCC | EMEM+10%FBS |
COLO829 | ATCC | RPMI1640+10%FBS |
DAUDI | ATCC | RPMI1640+10%FBS |
DU145 | ATCC | EMEM+10%FBS |
DU4475 | ATCC | RPMI1640+10%FBS |
HCC1419 | ATCC | RPMI1640+10%FBS |
HT1197 | ATCC | EMEM+10%FBS |
JEKO1 | ATCC | RPMI1640+20%FBS |
K562 | ATCC | IMDM+10%FBS |
KASUMI1 | ATCC | RPMI1640+10%FBS |
MCF7 | ATCC | EMEM+0.01mg/ml bovine insulin+10% FBS |
MDAMB415 | ATCC | Leibovitz's L-15+2mM L-Glutamine+10 mcg/ml insulin+10 mcg/ml glutathione+15% FBS |
MEG01 | ATCC | RPMI1640+10%FBS |
PC3 | ATCC | F-12K+10%FBS |
RAMOS2G64C10 | ATCC | RPMI1640+10%FBS |
RDES | ATCC | RPMI1640+15%FBS |
REC1 | ATCC | RPMI1640+10%FBS |
REH | ATCC | RPMI1640+10%FBS |
SBC5 | JCRB | EMEM+10%FBS |
SH4 | ATCC | DMEM+10%FBS |
SKES1 | ATCC | McCoy′s 5A+15%FBS |
SKMEL28 | ATCC | EMEM+10%FBS |
SKMEL3 | ATCC | McCoy′s 5A+15%FBS |
SUPB15 | ATCC | IMDM+4mM L-glutamine+1.5 g/L sodium bicarbonate+0.05 mM 2-mercaptoethanol+20% FBS |
WERIRR1 | ATCC | RPMI1640+10%FBS |
WM115 | ATCC | EMEM+10%FBS |
Results: as shown in fig. 4, uveal melanoma, hematological cancer, prostate cancer, breast cancer, and ewing's sarcoma cell lines were more sensitive to BRG1/BRM inhibition than the other cell lines tested. Inhibition of uveal melanoma, hematological cancer, prostate cancer, breast cancer, and ewing's sarcoma cell line was maintained until day 7.
Example 11 influence of BRG1/BRM ATPase inhibition on growth of cancer cell lines
The procedure is as follows: the combined cell viability assay was performed using PRI SM (while analyzing relative inhibition in the mixture) as previously described ("High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell line s",Yu et al, nature Biotechnology 34,419-423,2016, with the following modifications. Cell lines were obtained from Cancer Cell Line Encyclopedia (CCLE) collections and were adapted to phenol red-free RPMI-1640 medium supplemented with 10% heat-inactivated Fetal Bovine Serum (FBS) to apply unique infection and pooling protocols to such large cell line collections. A lentiviral rotainfection protocol was performed to introduce 24 nucleotide barcodes into each cell line, with an estimated multiplicity of infection (MOI) of 1 for all cell lines, using blasticidin as a selectable marker. Then, more than 750 stable barcoded PRISM cancer cell lines were pooled together according to doubling time, 25 cancer cell lines in pool (pool). For the screening performance, instead of plating a pool of 25 cell lines into each well as previously described (Yu et al), all adherent cell lines or all suspension cell line pools were plated together using T25 flasks (100,000 cells/flask) or 6 well plates (50,000 cells/well), respectively. Cells were treated with DMSO or compound at 8 spots in triplicate, starting at a maximum concentration of 10 μm, with a 3-fold dose response. As a control for assay robustness, two previously validated compounds were used: the pan Raf inhibitor AZ-628 and the proteasome inhibitor bortezomib were used to treat cells in parallel with the highest concentrations of 2.5. Mu.M and 0.039. Mu.M, respectively.
After 3 days of treatment with the compounds, the cells were lysed, genomic DNA was extracted, barcodes amplified by PCR and detected with next generation sequencing. Cell viability was determined by comparing the cell line specific barcode count in the treated samples to the cell line specific barcode count in DMSO control and day 0 control. A dose response curve was fitted to each cell line, the corresponding area under the curve (AUC) was calculated and compared to the median AUC for all cell lines (fig. 5).
Results: cell lines with AUC less than the median are considered to be most sensitive.
Example 12 effect of brg1/BRM atpase inhibitors on the growth of uveal melanoma cell lines.
The procedure is as follows: the uveal melanoma cell lines (92-1, MP41, MP38, MP 46) and non-small cell lung cancer cells (NCIH 1299) were plated into 96-well plates with growth medium (see Table 2). BRG1/BRM ATPase inhibitor compound B is dissolved in DMSO and added to the cells at the time of plating at a concentration gradient of 0 to 10. Mu.M. Cells were incubated at 37℃for 3 days. Three days after treatment, cell growth was measured with Cell-titer glow (Promega) and luminescence read on an Envision plate reader (PERKIN ELMER).
Results: as shown in fig. 6, compound B resulted in effective growth inhibition of the cell line.
Example 13 comparison of BRG1/BRM inhibitor with clinical PKC and MEK inhibitors in uveal melanoma cell lines
The procedure is as follows: the uveal melanoma cell line 92-1 or MP41 was plated into 96-well plates in the presence of growth medium (see table 2). BAF atpase inhibitor (compound B), PKC inhibitor (LXS 196; medChemExpress) and MEK inhibitor (semitinib; SELLECK CHEMICALS) were dissolved in DMSO and added to cells at the time of plating in a concentration gradient of 0 to 10 μm. Cells were incubated at 37℃for 3 days. Three days after treatment, cell growth was measured with Cell-titer glow (Promega) and luminescence read on an Envision plate reader (PERKIN ELMER).
Results: as shown in fig. 7 and 8, compound B showed a more potent effect on the growth inhibition of uveal melanoma cells compared to clinical PKC and MEK inhibitors. Furthermore, compound B was found to undergo growth inhibition faster than clinical PKC and MEK inhibitors.
Example 14 brg1/BRM atpase inhibitors are effective in inhibiting the growth of PKC inhibitor resistant cells.
The procedure is as follows: MP41 uveal melanoma cells were made tolerant to PKC inhibitors (LXS 196; medChemExpress) by prolonged culture in growth medium (see Table 2) containing increasing concentrations of the compound (up to 1. Mu.M). After 3 months, the sensitivity of the parental MP41 cells and PKC inhibitor (PKCi) resistant cells to either PKC inhibitor (LXS 196) or BRG1/BRM atpase inhibitor (compound B) was tested in a 7 day growth inhibition assay as described in example 6 above.
Results: although PKCi-resistant cells were able to tolerate growth at higher concentrations of LXS196 than the parental MP41 cell line (fig. 9), BRG1/BRM atpase inhibitors (compound B) produced strong growth inhibition on both PKCi-resistant and parental cell lines (fig. 10). PKCi-resistant cells were more sensitive to compound B than the parental MP41 cells (fig. 10).
EXAMPLE 15 Synthesis of Compound C
BRG1/BRM inhibitor compound C has the following structure:
Compound C was synthesized as shown in scheme 5 below.
Scheme 5 Synthesis of Compound C
In the ATPase assay described above, compound C was found to have an IP 50 for BRM and 1.3nM for BRG1, respectively.
Example 16 brg1/BRM atpase inhibitors cause inhibition of uveal melanoma tumor growth in vivo.
The procedure is as follows: 5X10 6 92-1 uveal melanoma cells in 50% matrigel were subcutaneously implanted in the armpit area of nude mice (Envigo). Tumors were allowed to grow to an average of about 200mm 3 at which time mice were grouped and dosing was started. Mice were given vehicle (20% 2-hydroxypropyl- β -cyclodextrin) or increasing doses of compound C once daily by oral gavage. Tumor volumes and body weights were measured over the course of 3 weeks and dosages were adjusted according to body weight to achieve the appropriate dosages in mg/kg. At this point, the animals were sacrificed, tumors were dissected and imaged.
Results: as shown in fig. 11 and 12, treatment with compound C resulted in inhibition of tumor growth in a dose-dependent manner, with tumor regression observed at the highest (50 mg/kg) dose. As shown in fig. 13, all treatments were well tolerated and no weight loss was observed (fig. 13).
Example 17 effect of BRG1/BRM ATPase inhibition on the growth of uveal melanoma and hematological cancer cell lines
The procedure is as follows: uveal melanoma cell lines (92-1, MEL202, MP41, MP38, MP 46), prostate cancer cells (22 RV 1), acute leukemia cells (EOL 1, THP 1) and histiocyte lymphoma cells (U937) were plated into 96-well plates with growth medium (see table 2). BRG1/BRM atpase inhibitor, N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide are dissolved in DMSO and added to cells at the time of plating in a concentration gradient of 0 to 2 μm (for uveal melanoma) or 0 to 1 μm (for other cell lines). Cells were incubated at 37℃for 3 days. Three days after treatment, cell growth was measured with Cell-titer glow (Promega) and luminescence read on an Envision plate reader (PERKIN ELMER).
Results: as shown in fig. 14, N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide gave effective growth inhibition in all cell lines. As shown in table 3, the measured absolute IC 50 values for all cell lines tested were below 350 nanomolar.
Table 3 lists the cell lines tested, the growth medium used and the absolute IC 50 values (nM) after 3 days of compound treatment.
TABLE 3 cell lines, growth Medium and absolute IC 50 values
Example 18 inhibition of brg1/BRM atpase causes inhibition of uveal melanoma tumor growth in vivo.
The procedure is as follows: 5X10 6 92-1 uveal melanoma cells in 50% matrigel were subcutaneously implanted in the armpit area of nude mice (Envigo). Tumors were allowed to grow to an average of about 200mm 3 at which time mice were grouped and dosing was started. Mice were given vehicle (20% 2-hydroxypropyl- β -cyclodextrin) or increasing doses of N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide once daily by oral gavage. Tumor volumes and body weights were measured over the course of 3 weeks and dosages were adjusted according to body weight to achieve the appropriate dosages in mg/kg.
Results: as shown in fig. 15, treatment with N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide resulted in inhibition of tumor growth in a dose-dependent manner, tumor regression being observed at the highest (1.5 mg/kg) dose. As shown in fig. 16, all treatments were well tolerated depending on the observed weight change.
Example 19 combination of FHD-286 and alpha PD-1Ab provides synergistic benefits in an immunocompromised B16F10 melanoma model
The procedure is as follows: B16F10 cells were implanted into mice and tumors were grown to 50mm 3. Mice were treated with 1.5mg/kg daily of N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide and 10mg/kg twice weekly of anti-PD-1 antibody.
Results: as shown in fig. 17-19, the combination of BRM/BRG1 inhibitor and anti-PD-1 antibody produced more than additive effects on tumor inhibition and survival in this model.
Example 20 combination of BRM/BRG1 inhibitor and PD-1 inhibitor provides synergistic benefits in A20 lymphoma tumor bearing mice
The procedure is as follows: a20 cells were implanted into mice and tumors were grown to 50mm 3. Mice were treated with 1.5mg/kg daily of N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide and 10mg/kg twice weekly of anti-PD-1 antibody.
Results: as shown in fig. 20-22, the combination of BRM/BRG1 inhibitor and anti-PD-1 antibody produced more than additive effects on tumor inhibition and survival in this model.
Example 21 combination of BRM/BRG1 inhibitor and PD-1 inhibitor provides synergistic benefits in CT26 colorectal tumor-bearing mice
The procedure is as follows: CT26 cells were implanted into mice and tumors were grown to 50mm 3. Mice were treated with 1.5mg/kg daily of N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide and 10mg/kg twice weekly of anti-PD-1 antibody.
Results: as shown in fig. 23-25, in this model, the combination of BRM/BRG1 inhibitor and anti-PD-1 antibody produced more than additive effects on tumor inhibition and survival.
Example 22 combination of BRM/BRG1 inhibitor and PD-L1 inhibitor provides synergistic benefits in CT26 colorectal tumor-bearing mice
The procedure is as follows: CT26 cells were implanted into mice and tumors were grown to 50mm 3. Mice were treated with 1.5mg/kg daily of N- ((S) -1- ((4- (6- (cis-2, 6-dimethylmorpholino) pyridin-2-yl) thiazol-2-yl) amino) -3-methoxy-1-oxopropan-2-yl) -1- (methylsulfonyl) -1H-pyrrole-3-carboxamide and 10mg/kg twice weekly of anti-PD-L1 antibody.
Results: as shown in fig. 26-27, in this model, the combination of BRM/BRG1 inhibitor and anti-PD-L1 antibody produced more than additive effects on tumor inhibition and survival.
Other embodiments
1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of an agent that reduces the level and/or activity of BRM and/or BRG1 and an effective amount of immunotherapy.
2. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having the structure:
/>
Or a pharmaceutically acceptable salt thereof, and an effective amount of an immunotherapy.
3. The method of embodiment 1 or 2, wherein the immunotherapy is administered concurrently with the agent or the compound or a pharmaceutically acceptable salt thereof.
4. The method of embodiment 1 or 2, wherein the immunotherapy is administered prior to the agent or the compound or a pharmaceutically acceptable salt thereof.
5. The method of embodiment 1 or 2, wherein the immunotherapy is administered after the agent or the compound or a pharmaceutically acceptable salt thereof.
6. The method of any one of embodiments 1 to 5, wherein the immunotherapy is a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a CD-161 inhibitor, or an adoptive T cell transfer therapy.
7. The method of embodiment 6, wherein the immunotherapy is a CTLA-4 inhibitor.
8. The method of embodiment 6, wherein the immunotherapy is a PD-1 inhibitor.
9. The method of embodiment 6, wherein the immunotherapy is a PD-L1 inhibitor.
10. The method of embodiment 6, wherein the immunotherapy is a CD-161 inhibitor.
11. The method of embodiment 6, wherein the immunotherapy is adoptive T cell transfer therapy.
12. The method of any one of embodiments 1-11, wherein the cancer fails to respond to a previously administered immunotherapy.
13. The method of any one of embodiments 1 to 12, wherein the cancer is resistant to immunotherapy.
14. The method of any one of embodiments 1 to 13, wherein the cancer does not comprise a mutation that results in loss of BAF complex function.
15. The method of any one of embodiments 1 to 14, wherein the effective amount of the agent or the compound is an amount effective to increase the level of activated T cells in the subject.
16. The method of embodiment 15, wherein the effective amount of the agent or the compound is an amount effective to increase the level of activated T cells in a tumor microenvironment.
17. The method of any one of embodiments 1-16, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, primary focus unknown tumor, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal gastric cancer, esophageal cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenal cortex cancer, appendiceal cancer, small intestine cancer, penile cancer, bone cancer, or hematological cancer.
18. The method of embodiment 17, wherein the cancer is esophageal cancer.
19. The method of embodiment 18, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, primary foci-less tumor, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, penile cancer, bone cancer, renal cell carcinoma, prostate cancer, or hematological cancer.
20. The method of embodiment 19, wherein the cancer is non-small cell lung cancer.
21. The method of embodiment 19, wherein the cancer is melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer.
22. The method of embodiment 21, wherein the cancer is melanoma.
23. The method of embodiment 22, wherein the melanoma is uveal melanoma, mucosal melanoma, or cutaneous melanoma.
24. The method of embodiment 23, wherein the melanoma is uveal melanoma.
25. The method of embodiment 21, wherein the cancer is prostate cancer.
26. The method of embodiment 21, wherein the cancer is hematological cancer.
27. The method of embodiment 26, wherein the hematological cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myelogenous leukemia, myelodysplastic syndrome, immunoglobulin a lambda myeloma, diffuse tissue cell and lymphocyte mixed lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-hodgkin's lymphoma.
28. The method of embodiment 21, wherein the cancer is breast cancer.
29. The method of embodiment 28, wherein the breast cancer is ER positive breast cancer, ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer.
30. The method of embodiment 21, wherein the cancer is bone cancer.
31. The method of embodiment 30, wherein the bone cancer is ewing's sarcoma.
32. The method of embodiment 21, wherein the cancer is renal cell carcinoma.
33. The method of embodiment 32, wherein the renal cell carcinoma is a microocular deformity transcription factor family translocating renal cell carcinoma.
34. The method according to any one of embodiments 1 to 33, wherein the cancer expresses BRG1 and/or BRM proteins.
35. The method of any one of embodiments 1 to 34, wherein the subject or the cancer has a BRG1 loss-of-function mutation.
36. The method of embodiment 35, wherein the BRG1 loss-of-function mutation is in the atpase catalytic domain of the protein.
37. The method of embodiment 35, wherein the BRG1 loss-of-function mutation is a deletion at the C-terminus of BRG 1.
38. The method of any one of embodiments 1 to 37, wherein the cancer does not have or has been determined to have no epidermal growth factor receptor mutation and/or anaplastic lymphoma kinase drive factor mutation.
39. The method of any one of embodiments 1to 38, wherein the cancer has or has been determined to have a KRAS mutation, a GNAQ mutation, a GNA11 mutation, a PLCB4 mutation, a CYSLTR mutation, a BAP1 mutation, a SF3B1 mutation, an EIF1AX mutation, a TFE3 translocation, a TFEB translocation, a MITF translocation, an EZH2 mutation, a SUZ12 mutation, and/or an EED mutation.
40. The method of any one of embodiments 1-39, wherein the cancer is metastatic.
41. The method of any one of embodiments 1-40, wherein the cancer is resistant to or fails to respond to prior treatment with an anti-cancer therapy.
42. The method of embodiment 41, wherein the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, thermotherapy, or photocoagulation, or a combination thereof.
43. The method of embodiment 42, wherein the anti-cancer therapy is a chemotherapeutic agent or a cytotoxic agent.
44. The method of embodiment 43, wherein the chemotherapeutic agent or cytotoxic agent is a mitogen-activated protein kinase (MEK) inhibitor and/or a Protein Kinase C (PKC) inhibitor.
45. The method of any one of embodiments 1-44, wherein the cancer is resistant to or fails to respond to prior treatment with an anticancer therapy.
46. The method of any one of embodiments 1-45, wherein the method further comprises administering an anti-cancer therapy to the subject.
47. The method of embodiment 46, wherein the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, thermotherapy, or photocoagulation, or a combination thereof.
48. The method of embodiment 46 or 47, wherein the anti-cancer therapy is surgery, a MEK inhibitor and/or a PKC inhibitor, or a combination thereof.
49. The method of embodiment 48, wherein the MEK inhibitor is semantenib, bimatinib, or tramatinib.
50. The method of embodiment 48, wherein the PKC inhibitor is cord Qu Tuolin or IDE196.
51. An agent that reduces the level and/or activity of BRM and/or BRG1 for use in combination with immunotherapy for treating cancer in a subject in need thereof.
52. A compound having the structure:
Or a pharmaceutically acceptable salt thereof, for use in combination with immunotherapy to treat cancer in a subject in need thereof.
53. Use of an agent that reduces the level and/or activity of BRM and/or BRG1 for the manufacture of a medicament for use in combination with immunotherapy for the treatment of cancer in a subject in need thereof.
54. A compound having the structure:
Or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in combination with immunotherapy for treating cancer in a subject in need thereof.
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. When a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein serves as the definition of the term.
While the invention has been described in connection with specific embodiments thereof, it should be understood that,
The application is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the application following, in general, the principles of the application and including such departures from the present disclosure as come within known or customary practice within the art to which the application pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.
Claims (52)
1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of an agent that reduces the level and/or activity of BRM and/or BRG1 and an effective amount of immunotherapy.
2. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having the structure:
Or a pharmaceutically acceptable salt thereof, and an effective amount of an immunotherapy.
3. The method of claim 1 or 2, wherein the immunotherapy is administered concurrently with the agent or the compound or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 or 2, wherein the immunotherapy is administered prior to the agent or the compound or a pharmaceutically acceptable salt thereof.
5. The method of claim 1 or 2, wherein the immunotherapy is administered after the agent or the compound or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 or 2, wherein the immunotherapy is CTLA-4 inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CD-161 inhibitor, or adoptive T cell transfer therapy.
7. The method of claim 6, wherein the immunotherapy is a CTLA-4 inhibitor.
8. The method of claim 6, wherein the immunotherapy is a PD-1 inhibitor.
9. The method of claim 6, wherein the immunotherapy is a PD-L1 inhibitor.
10. The method of claim 6, wherein the immunotherapy is a CD-161 inhibitor.
11. The method of claim 6, wherein the immunotherapy is adoptive T cell transfer therapy.
12. The method of claim 1 or 2, wherein the cancer fails to respond to a previously administered immunotherapy.
13. The method of claim 1 or 2, wherein the cancer is resistant to immunotherapy.
14. The method of claim 1 or 2, wherein the cancer does not comprise a mutation that results in loss of BAF complex function.
15. The method of claim 1 or 2, wherein the effective amount of the agent or the compound is an amount effective to increase the level of activated T cells in the subject.
16. The method of claim 15, wherein the effective amount of the agent or the compound is an amount effective to increase the level of activated T cells in a tumor microenvironment.
17. The method of claim 1 or 2, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, primary foci-less tumor, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal gastric cancer, esophageal cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell cancer, bone cancer, non-hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenal cortex cancer, appendiceal cancer, small intestine cancer, penile cancer, bone cancer, or hematological cancer.
18. The method of claim 17, wherein the cancer is esophageal cancer.
19. The method of claim 18, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, primary foci-less tumor, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, penile cancer, bone cancer, renal cell cancer, prostate cancer, or hematological cancer.
20. The method of claim 19, wherein the cancer is non-small cell lung cancer.
21. The method of claim 19, wherein the cancer is melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer.
22. The method of claim 21, wherein the cancer is melanoma.
23. The method of claim 22, wherein the melanoma is uveal melanoma, mucosal melanoma, or cutaneous melanoma.
24. The method of claim 23, wherein the melanoma is uveal melanoma.
25. The method of claim 21, wherein the cancer is prostate cancer.
26. The method of claim 21, wherein the cancer is a hematologic cancer.
27. The method of claim 26, wherein the hematological cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myelogenous leukemia, myelodysplastic syndrome, immunoglobulin a lambda myeloma, diffuse tissue cell and lymphocyte mixed lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-hodgkin's lymphoma.
28. The method of claim 21, wherein the cancer is breast cancer.
29. The method of claim 28, wherein the breast cancer is ER positive breast cancer, ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer.
30. The method of claim 21, wherein the cancer is bone cancer.
31. The method of claim 30, wherein the bone cancer is ewing's sarcoma.
32. The method of claim 21, wherein the cancer is renal cell carcinoma.
33. The method of claim 32, wherein the renal cell carcinoma is a microphthalmia transcription factor family translocating renal cell carcinoma.
34. The method of claim 1 or 2, wherein the cancer expresses BRG1 and/or BRM proteins.
35. The method of claim 1 or 2, wherein the subject or the cancer has a BRG1 loss-of-function mutation.
36. The method of claim 35, wherein the BRG1 loss-of-function mutation is in the atpase catalytic domain of the protein.
37. The method of claim 35, wherein the BRG1 loss-of-function mutation is a deletion at the C-terminus of BRG 1.
38. The method of claim 1 or 2, wherein the cancer does not have or has been determined to have no epidermal growth factor receptor mutation and/or anaplastic lymphoma kinase-driving factor mutation.
39. The method of claim 1 or 2, wherein the cancer has or has been determined to have a KRAS mutation, a GNAQ mutation, a GNA11 mutation, a PLCB mutation, a CYSLTR2 mutation, a BAP1 mutation, a SF3B1 mutation, an EIF1AX mutation, a TFE3 translocation, a TFEB translocation, a MITF translocation, an EZH2 mutation, a SUZ12 mutation, and/or an EED mutation.
40. The method of claim 1 or 2, wherein the cancer is metastatic.
41. The method of claim 1 or 2, wherein the cancer is resistant to or fails to respond to prior treatment with an anti-cancer therapy.
42. The method of claim 41, wherein the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, thermotherapy, or photocoagulation, or a combination thereof.
43. The method of claim 42, wherein the anti-cancer therapy is a chemotherapeutic agent or a cytotoxic agent.
44. The method of claim 43, wherein the chemotherapeutic agent or cytotoxic agent is a mitogen-activated protein kinase (MEK) inhibitor and/or a Protein Kinase C (PKC) inhibitor.
45. The method of claim 1 or 2, wherein the cancer is resistant to or fails to respond to prior treatment with a PKC inhibitor.
46. The method of claim 1 or 2, wherein the method further comprises administering an anti-cancer therapy to the subject.
47. The method of claim 46, wherein the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, thermotherapy, or photocoagulation, or a combination thereof.
48. The method of claim 46, wherein the anti-cancer therapy is surgery, a MEK inhibitor and/or a PKC inhibitor, or a combination thereof.
49. The method of claim 48, wherein the MEK inhibitor is semantenib, bimatinib, or tramatinib.
50. The method of claim 48, wherein the PKC inhibitor is cord Qu Tuolin or IDE196.
51. An agent that reduces the level and/or activity of BRM and/or BRG1 for use in combination with immunotherapy for treating cancer in a subject in need thereof.
52. A compound having the structure:
Or a pharmaceutically acceptable salt thereof, for use in combination with immunotherapy to treat cancer in a subject in need thereof.
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