WO2023192505A2 - Procédé de traitement du cancer avec un inhibiteur d'enzyme de réparation de dommages à l'adn - Google Patents

Procédé de traitement du cancer avec un inhibiteur d'enzyme de réparation de dommages à l'adn Download PDF

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Publication number
WO2023192505A2
WO2023192505A2 PCT/US2023/016940 US2023016940W WO2023192505A2 WO 2023192505 A2 WO2023192505 A2 WO 2023192505A2 US 2023016940 W US2023016940 W US 2023016940W WO 2023192505 A2 WO2023192505 A2 WO 2023192505A2
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cancer
cell
tumor
inhibitor
carcinoma
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PCT/US2023/016940
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WO2023192505A3 (fr
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Eckard Weber
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Primefour Therapeutics, Inc.
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Publication of WO2023192505A3 publication Critical patent/WO2023192505A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present disclosure is in the field of medicinal chemistry.
  • the disclosure provides a method for treating cancer by administering a reverse transcriptase inhibitor (RTI), that is also a DNA polymerase theta (PolQ) inhibitor to a patient in need thereof whose cancer cells have a deficiency or is suspected of having a deficiency of a DNA repair enzyme.
  • RTI reverse transcriptase inhibitor
  • PolQ DNA polymerase theta
  • RTIs include lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), tenofovir alafenamide, zidovudine (AZT), didanosine (ddl), tenofovir disoproxil, adefovir dipivoxil, entecavir (ETV), and telbivudine.
  • the RTI is a nucleoside reverse transciptase inhibitor (NRTI).
  • NRTI nucleoside reverse transciptase inhibitor
  • the disclosure also provides a method for treating cancer by administering a damage repair (DDR) enzyme inhibitor, e.g. a Pol ⁇ , Pol ⁇ , and/or Pol ⁇ inhibitor.
  • the cancer is breast, colon, lung, pancreatic ductal, prostate, ovarian, or head and neck cancer.
  • DSBs DNA double-strand breaks
  • HR homologous recombination
  • NHEJ non-homologous end-joining
  • alt-NHEJ alternative NHEJ
  • MMEJ Microhomology-mediated end-joining
  • HR-mediated repair is a high-fidelity mechanism essential for accurate error-free repair, preventing cancer-predisposing genomic stability.
  • NHEJ and MMEJ are error-prone pathways that can leave mutational scars at the site of repair.
  • MMEJ can function parallel to both HR and NHEJ pathways (Truong et al. PNAS 2013, 110 (19), 7720-7725). See also WO2021/123785.
  • PolQ UniProtKB - 075417 (DPOLQ HUMAN) as the key protein in MMEJ (Kent et al., Nature Structural & Molecular Biology’ (2015), 22(3), 230-237, Mateos-Gomez et al., Nature (2015), 518(7538), 254-257).
  • PolQ is multifunctional enzyme, which comprises an N-terminal helicase domain (SF2 HEL308-type) and a C-terminal low-fidelity DNA polymerase domain (A-type) (Wood & D bountye, DNA Repair (2016), 44, 22-32). Both domains have been shown to have concerted mechanistic functions in MMEJ.
  • the helicase domain mediates the removal of RPA protein from ssDNA ends and stimulates annealing.
  • the polymerase domain extends the ssDNA ends and fills the remaining gaps.
  • PolQ has been shown to be essential for the survival of HR-defective (HRD) cells (e.g. synthetic lethal with FA/BRCA-deficiency) and is up-regulated in HRD tumor cell lines (Ceccaldi et al.. Nature (2015), 518(7538), 258-262).
  • HRD HR-defective
  • PolQ inhibition prevents the MMEJ -dependent functional reversion of BRCA2 mutations that underlies the emergence of cisplatin and PARPi resistance in tumors.
  • DDR inhibitors e.g., a Pol ⁇ , Pol ⁇ , and/or Pol ⁇ inhibitor, for the treatment of cancer.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of a reverse transcriptase inhibitor (RTI) that is also a Pol ⁇ inhibitor, with the proviso that the RTI is not ddC (also known as zalcitabine or 2'-3 '-dideoxy cytidine).
  • RTI reverse transcriptase inhibitor
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of DDR enzyme, e.g., Pol0, inhibitor.
  • DDR enzyme e.g., Pol0, inhibitor.
  • a method of treating cancer in a patient wherein the cells of the cancer are suspected of or exhibit defi ciency of a DDR enzyme, comprising administering to the patient an effective amount of DDR enzyme, e.g., Pol0, inhibitor.
  • DDR enzyme e.g., Pol0, inhibitor.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of DDR enzyme, e.g., Pol0, inhibitor.
  • DDR enzyme e.g., Pol0, inhibitor.
  • a method of treating cancer in a patient wherein the cells of the cancer are suspected of or exhibit deficiency of a DNA repair enzyme, comprising administering to the patient an effective amount of DDR enzyme, e.g., PolG, inhibitor.
  • DDR enzyme e.g., PolG
  • the method further comprises administering a second agent that is a poly ADP ribose polymerase (PARI 5 ) inhibitor, an ATM inhibitor, a weel inhibitor, a CHK inhibitor, or an ATR inhibitor.
  • a second agent that is a poly ADP ribose polymerase (PARI 5 ) inhibitor, an ATM inhibitor, a weel inhibitor, a CHK inhibitor, or an ATR inhibitor.
  • the cells are resistant to PARP inhibition.
  • the second agent is a PARP inhibitor.
  • the PARP inhibitor is olaparib, rucaparib, niraparib or talazoparib.
  • the DDR enzyme is encoded by at least one homologous recombination (HR) gene.
  • the at least one HR gene is ATM, ,ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), FPEN, CDK12, MRE11, NBS 1, NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4 LIG1 , RPA1, BRIP1 or PTEN.
  • HR homologous recombination
  • the RTI is lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alafenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV), 2',3'-dideoxyguanosine (ddG), 2’,3’- dideoxyadenosine (ddA), 2'-fluoro-2',3'-dideoxyarabinosyladenine (F-ddA), efavirenz (EFV), nevirapine (NVP), abacavir (ABC), adefovir dipivoxil, or telbivudine.
  • the RTI and/or DNA damage repair enzyme inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt or solvate thereof, or
  • [0015] B is selected from the group consisting of
  • R 1 is selected from the group consisting of hydrogen and -OH;
  • R 2 is selected from the group consisting of methyl, ethynyl, and -CN;
  • R 3 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo and methyl;
  • R 4 is selected from the group consisting of -NH 2 and -OH;
  • R 3 is selected from the group consisting of -NH 2 and -OH;
  • R 6 is selected from the group consisting of hydrogen, fluoro, chloro, and -NH 2
  • the RTI and/or DNA damage repair enzyme inhibitor is a compound of Formula II: or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof, wherein R 1 , R”, R 3 , and R 4 are as defined in connection with Formula I.
  • the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R 3 is hydrogen.
  • the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R 3 is selected from the group consisting of fluoro and chloro. [0025] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R 3 is methyl.
  • the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R 4 is -NH 2 .
  • the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R 4 is -OH.
  • the RTI and/or DDR enzyme inhibitor is a compound of Formula III: or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof, wherein R 1 , R 2 , R 5 , and R° are as defined in connection with Formula I.
  • the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R 5 is -NH 2 .
  • the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R 5 is -OH.
  • the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R 6 is hydrogen.
  • the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R 6 is chloro.
  • the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R 6 is fluoro.
  • the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R 6 is -NH 2 .
  • the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R 1 is hydrogen.
  • the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R 1 is -OH.
  • the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R 2 is methyl.
  • the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R 2 is ethynyl.
  • the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R 2 is -CN.
  • the RTI and/or DDR enzyme inhibitor is any one or more of the compounds of Table A, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof
  • the RTI and/or DDR enzyme inhibitor is any one or more of the compounds of Table B, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof.
  • the RTI and/or DDR enzyme inhibitor is a compound Table A, Table B, or Table 3. See below.
  • the compound of Table A, Table B, or Table 3 is a RTI and a DDR enzyme inhibitor.
  • the compound of Table A, Table B, or Table 3 is a RTI inhibitor.
  • the compound of Table A, Table B, or Table 3 is a DDR enzyme inhibitor, e.g., one or more of the DDR enzymes of Table C.
  • the compound of Table A, Table B, or Table 3 is a Pol ⁇ inhibitor.
  • the compound of Table A, Table B, or Table 3 is a Pol ⁇ inhibitor.
  • the compound of Table A, Table B, or Table 3 is a Pol ⁇ inhibitor.
  • the compound of Table A, Table B, or Table 3 is a Pol ⁇ inhibitor.
  • the DDR enzyme inhibitor is a compound of Table 3.
  • the cancer i s breast cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCAI and/or BRCA2 genes.
  • the cancer is prostate cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and or BRCA2 genes.
  • the cancer is ovarian cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCAI and /or BRCA2 genes.
  • the cancer is pancreatic cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCAI and/or BRCA2 genes.
  • the cells of the cancer exhibit overexpression of PolQ compared to the corresponding cells that are not cancer cells.
  • the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitor ⁇ ' concentration of less than 100 nM in a HeLa cell-based dualluciferase assay. In some embodiments, the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitory concentration of less than 50 nM in a HeLa cell-based dualluciferase assay. In some embodiments, the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitory concentration of less than 10 nM in a HeLa cell-based dualluciferase assay.
  • the method further comprises administering a therapeutically effective amount of at least one second therapeutic agent useful for treating the cancer.
  • the method is for the treatment of breast cancer, wherein the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afinitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemaciclib), Fareston®
  • Soltamox®
  • the method is for the treatment of colon cancer, wherein the at least one second therapeutic agent is Xeloda® (capecitabine), Eloxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta-lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy® (ipilmumab
  • the method is for the treatment of lung cancer, wherein the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfinizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
  • Etopophos® etoposide
  • Hycamtin® topotecan
  • VePesid® etoposide
  • Toposar® etoposide
  • Opdivo® nivolumab
  • Keytruda® pembrolizumab
  • the method is for the treatment of pancreatic ductal cancer, wherein the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
  • Gemzar® Gamcitabine
  • fluorouracil Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin
  • the method is for the treatment of head and neck cancer, wherein the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
  • the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
  • the method is for the treatment of prostate cancer, wherein the at least one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
  • Suprefact® buserelin
  • Firmagon® degarelix
  • Zoladex® goserelin
  • Vantas® histrelin
  • Eligard® leuprolide
  • Orgovyx® relugolix
  • Trelstar® triptorelin
  • Casodex® (bicalutamide),
  • the at least one second therapeutic agent is a STING agonist.
  • the patient is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
  • kits for carrying out the methods described herein comprising (i) a RTI and/or DDR enzyme inhibitor; and (ii) and instructions for administering the RTI and/or DDR enzyme inhibitor to a patient having cancer.
  • the kit contains instructions for administering the RTI and/or DDR enzyme inhibitor according to an intermittent dosing schedule.
  • the kit further comprises at least one second therapeutic agent for the treatment of cancer.
  • the kit further comprises instructions for administering the RTI and/or DDR enzyme inhibitor together with at least one second therapeutic agent for the treatment of cancer.
  • a method for treating cancer in patient in need thereof comprising administering a therapeutically effective amount of a reverse transcriptase inhibitor (RTI) that also inhibits PolQ, wherein the cells of the cancer are suspected of or exhibit deficiency of a DDR enzyme.
  • RTI reverse transcriptase inhibitor
  • the combination of, e.g., PolQ inhibition, and a deficiency of a DDR enzyme causes synthetic lethality to the cancer cells.
  • the deficiency is a reduction in the activity of a DDR enzyme.
  • the definiciency is an absence of activity of a DDR enzyme.
  • the deficiency of the DDR enzyme may be caused any means that results in the deficiency of the DDR enzyme including, but not limited to, genetic variations of the gene encoding the DDR enzyme including mutations (e.g. point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosome abnormalities. Copy Number Variation (CNV), epigenetics, DNA inversions, reduction in expression and mis-localisation.
  • a method of treating or preventing cancer in a patient in need thereof comprising administering a therapeutically effective amount of a DDR enzyme inhibitor to the patient.
  • the DDR enzyme inhibitor is one or more of the DDR enzymes of Table C. In another embodiment, the DDR enzyme inhibitor is a Pol ⁇ , Pol ⁇ , or Pol ⁇ inhibitor. In one embodiment, the DDR enzyme inhibitor is a Pol ⁇ (PolQ) inhibitor. In some embodiments, the cancer is a homologous recombinant (HR) deficient cancer.
  • said homologous recombination genes include any of: ATM, APR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBDI2), ERCC4 (BANCO), PTEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN SMARCA2, SMARCA4, LIGI , RPA 1, RPA2, BRI Pi and PTEN.
  • the disclosure provides a method for treating cancer in subject in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Table A, Table B, or Table 3, e.g., a compound of Table 3, wherein the cells of the cancer are suspected of or exhibit amplification of a DDR enzyme or gene.
  • a compound disclosed herein e.g., a compound of Table A, Table B, or Table 3, e.g., a compound of Table 3, wherein the cells of the cancer are suspected of or exhibit amplification of a DDR enzyme or gene.
  • DDR gene amplification e.g., overexpression, can lead to chemotherapy resistance and poor overall survival by augmenting DDR. See, e.g., Wu et al., Theranostics 10:3939- 3951 (2020).
  • Non-homologous end-joining deficiency refers to any genetic variation which results in a deficiency or loss of function of the resultant homologous recombination gene.
  • examples of said genetic variation include mutations (e.g. point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosome abnormalities, Copy Number Variation (CNV), epigenetics, DNA inversions, reduction in expression and mis-localisation.
  • said non-homologous end-joining genes are selected from any one or more of: LIG4, NHEJ1 , POLL, POLM, PRKDC, XRCC4, XRCC5, XRCC6, and DCLRE1C.
  • the RTI is islatravir, elvucitabine, lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alafenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV) or abacavir (ABC), wherein the RTI is administered according to an intermittent dosing schedule.
  • the RTI is abacavir (ZIAGENTM), abacavir/lamivudine (Epzicom), abacavir/lamivudine/zidovudine (TRIZIVIR TM ), adefovir, alovudine, amdoxovir, apricitabine, ATRIPLA®, BARACLUDE®, BIKT ARV Y®, COVIRACII.
  • the RTI is a LINE-1 inhibitor.
  • the RTI is islatravir, elvucitabine, lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alafenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV), 2',3’-dideoxyguanosine (ddG), 2', 3 '-dideoxyadenosine (ddA), 2'-fluoro-2',3 '-dideoxyarabinosyladenine (F-ddA), efavirenz (EFV), nevirapine (NVP), or abacavir (ABC).
  • the RTI is lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), tenofovir alafenamide, zidovudine (AZT), didanosine (ddl), tenofovir disoproxil, adefovir dipivoxil, entecavir (ETV), or telbivudine.
  • the RTI is islatravir.
  • the RTI is lamivudine (3TC).
  • the RTI is stavudine (d4T).
  • the RTI is emtricitabine (FTC).
  • the RTI is abacavir (ABC).
  • the RTI is tenofovir alafenamide.
  • the RTI is zidovudine (AZT).
  • the RTI is didanosine (ddl).
  • the RTI is tenofovir disoproxil.
  • the RTI is adefovir dipivoxil. [0081] In another embodiment, the RTI is entecavir.
  • the RTI is telbivudine.
  • cancer e.g., breast, colon, king, pancreatic ductal, prostate, ovarian, or head and neck cancer
  • Elvucitabine is a compound having the following chemical structure:
  • RTI reverse transcriptase inhibitor
  • IC 50 a nucleoside or nucleotide reverse transcriptase inhibitor.
  • RTIs inhibit human reverse transcriptase activity, e.g., with an IC 50 of about 50 ⁇ M or less, a suitable assay, e.g., a colorimetric enzyme immunoassay.
  • the IC 50 is 1 ⁇ M or less.
  • the IC 50 is 0,5 ⁇ M or less.
  • the IC 50 is 0.25 ⁇ M or less.
  • the IC 50 is 0.15 ⁇ M or less.
  • the IC 50 is 0.1 ⁇ M or less.
  • the IC 50 is 0.05 ⁇ M or less. In another embodiment, the IC 50 is 0.01 ⁇ M or less. In another embodiment, the IC 50 is 0.005 ⁇ M or less.
  • the RTI a nucleoside reverse transcriptase inhibitor (NRTI). In some embodiments, the RTI a nucleotide reverse transcriptase inhibitor. In some embodiments, the RTI is also a LINE-1 inhibitor.
  • DNA repair enzyme inhibitor or "DDR enzyme inhibitor” and the like as used herein refers to a compound that inhibits the activity of one or more human DNA damage repair enzymes with a half-maximal inhibitory concentration (IC 50 ) of 100 ⁇ M or less.
  • a DDR enzyme inhibitor inhibits human DDR enzyme activity an IC 50 of 10 ⁇ M or less.
  • a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC 50 of 1 ⁇ M or less.
  • a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC 50 of 500 nM or less.
  • a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC 50 of 100 nM or less.
  • a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC 50 of 50 nM or less. In another embodiment, a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC 50 of 10 nM or less.
  • Representative DDR enzymes are encoded by genes provided in Table Al . Representative DDR inhibitors are provided, for example, in Table 3.
  • the compounds disclosed herein may be phosphorylated in a cell by the addition of one, two, or three phosphate groups to form the corresponding mono, di-, or triphosphates as shown in Scheme 1 for Cpd. No. 2:
  • these phosphorylated compounds inhibit DDR enzymes following admistration to a subject.
  • these compounds can be used, for example, to treat or prevent cancers wherein DDR enzymes play a causative role.
  • cancer cells often acquire mutations in DDR genes, making them dependent on remaining DNA repair pathways.
  • Dependence on TMEJ for example, is characterized by an increased Pol ⁇ expression and is associated with poor patient prognosis.
  • Inhibition of Pol ⁇ in Pol ⁇ -dependent cancers leads to synthetic lethality. This is well described for malignancies deficient in homologous recombination, e.g., due to mutations in BRCA1 or BRCA2. See, e.g., Schrempt et al., Trends in Cancer 7:98-111 (2021) https://d0i.0rg/l 0.1016/j .trecan.2020.09.007.
  • a Compound of the Disclosure is synthetic lethal in cancers with HR or NHEJ deficiency
  • PolQ inhibitor or " Pol ⁇ inhibitor” as used herein refers to a compound that inhibits human PolQ activity with a half-maximal inhibitory/ concentration (IC50) of 100 nM or less. In some embodiments, the PolQ inhibitor inhibits PolQ activity with an IC 50 of less than 50 nM. In other embodiments, the PolQ inhibitor inhibits PolQ activity with an IC 50 of less than 10 nM.
  • a PolQ inhibitor assay is disclosed in WO2021/123785, the disclosure of which is fully incorporated by reference.
  • the phosphorylated species of the compounds disclosed herein, see Scheme 1 are POLQ inhibitors.
  • the triphosphates of the compounds disclosed herein are POLQ inhibitors. Representative triphosphates (TP) of the compounds disclosed herein are provided in Table 1 A.
  • LINE-1 inhibitor refers to a compound that inhibits human LINE-1 retrotransposition, e.g., with an IC 50 of about 50 ⁇ M or less in a HeLa cellbased dual -luciferase assay. See also Jones et al., (2008) PLoS ONE 3(2): el 547. doi:10.1371/joumal. pone.0001547; Xie et al., (2011) Nucleic Acids Res. 39(3): e!6. doi: 10.1093/nar/gkql076.
  • the IC 50 is 1 ⁇ M or less.
  • the IC 50 is 0.5 ⁇ M or less.
  • the IC 50 is 0.25 ⁇ M or less. In another embodiment, the IC 50 is 0.15 ⁇ M or less. In another embodiment, the IC50 is 0.1 ⁇ M or less. In another embodiment, the IC 50 is 0.05 ⁇ M or less. In another embodiment., the IC 50 is 0.01 ⁇ M or less. In another embodiment, the IC 50 is 0.005 ⁇ M or less.
  • the LINE-1 inhibitor is also a nucleoside reverse transcriptase inhibitor (NRTI). In some embodiments, the LINE-1 inhibitor is also a PolQ inhibitor.
  • Non-limiting exemplary LINE-1 inhibitors are described, for example, in WO 2020/154656 and Banuelos-Sanchez et al., Cell Chemical Biology 26:1095-1109 (2019).
  • Non-limiting exemplary LINE-1 inhibitors include islatravir, elvucitabine, lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alaphenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV), 2',3'-dideoxyguanosine (ddG), 2', 3 '-dideoxyadenosine (ddA), 2'-fluoro-2',3 '-dideoxyarabinosy ladenine (F-ddA), efavirenz (EFV), nevirapine (NVP), and abacavir (AB
  • biological sample refers any tissue or fluid from a subject that is suitable for detecting a biomarker.
  • useful biological samples include, but are not limited to, biopsi ed tissues and/or cells, e.g., lymph gland, inflamed tissue, tissue and/or cells involved in a condition or disease, blood, plasma, serous fluid, cerebrospinal fluid, saliva, urine, lymph, cerebral spinal fluid, and the like.
  • Other suitable biological samples will be familiar to those of ordinary skill in the relevant arts.
  • a biological sample can be analyzed for the expression level of a biological compound, e.g., POLQ, using any technique known in the art.
  • PCR polymerase chain reaction
  • RT-PCR reverse transcription-polymerase chain reaction
  • clg-FISH cytoplasmic light chain immunofluorescence combined with fluorescence in situ hybridization
  • intermittent dose administration refers to non-continuous administration of a RTI and/or DDR enzyme inhibitor to a subject.
  • Intermittent dose administration regimens useful in the present disclosure encompass any discontinuous administration regimen that provides a therapeutically effective amount of a RTI and/or DDR enzyme inhibitor to a subject in need thereof.
  • Intermittent dosing regimens can use equivalent, lower, or higher doses of a RTI and/or DDR enzyme inhibitor than would be used in continuous dosing regimens.
  • Advantages of intermittent dose administration include, but are not limited to, improved safety, decreased toxicity, e.g., decreased weight loss, increased exposure, increased efficacy, and/or increased subject compliance. These advantages may be realized when a RTI and/or DDR enzyme inhibitor is administered as a single agent or when administered in combination with one or more additional therapeutic agents, e.g., a STING agonist.
  • Examples of treatable cancers include, but are not limited to, any one or more of the cancers of Table I .
  • the cancer is a solid tumor.
  • the cancer a hematological cancer.
  • Exemplary hematological cancers include, but are not limited to, the cancers listed in Table 2.
  • the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.
  • the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MLL).
  • the cancer is NUT-midline carcinoma.
  • the cancer is multiple myeloma.
  • the cancer is a lung cancer such as small cell lung cancer (SCLC).
  • SCLC small cell lung cancer
  • the cancer is a neuroblastoma.
  • the cancer is Burkitt’s lymphoma.
  • the cancer is cervical cancer.
  • the cancer is esophageal cancer.
  • the cancer is ovarian cancer.
  • the cancer is colorectal cancer.
  • the cancer is prostate cancer.
  • the cancer is breast cancer.
  • the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, breast cancer, bladder cancer, ovary' cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.
  • islatravir is administered to a subj ect in need thereof to treat breast, colon, lung, pancreatic ductal, prostate, ovarian, or head and neck cancer.
  • the cancer is breast cancer.
  • the cancer is colon cancer.
  • the cancer is lung cancer, e.g., small cell lung cancer or non-small cell lung cancer.
  • the cancer is pancreatic ductal cancer.
  • the cancer is prostate cancer.
  • the cancer is ovarian cancer.
  • the cancer is head and neck cancer.
  • the cells of the cancer overexpress one or more DDR enzymes.
  • the cells of the cancer overexpress one or more enzymes encoded by the genes of Table Bl.
  • the cells of the cancer overexpress one or more DDR enzymes of Table C.
  • the cancer overexpresses Pol ⁇ .
  • the cancer overexpresses Pol ⁇ .
  • the cancer overexpresses Pol g.
  • the cancer overexpresses TdT.
  • the cancer overexpresses POLQ.
  • the cancer is breast cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and/or BRCA2 genes.
  • the cancer is prostate cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and or BRCA2 genes.
  • the cancer is ovarian cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and /or BRCA2 genes.
  • the cancer is pancreatic cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and/or BRCA2 genes.
  • the patient is also administered at least one second therapeutic agent useful for the treatment of cancer.
  • the second therapeutic agent useful for the treatment of cancer is is a poly ADP ribose polymerase (PARP) inhibitor, an ATM inhibitor, a weel inhibitor, a CHK inhibitor, or an ATR inhibitor.
  • PARP poly ADP ribose polymerase
  • the PARP inhibitor is olaparib, rucaparib, niraparib or talazoparib.
  • the ATM inhibitor is AZD0156 or M3541 .
  • the ATR inhibitor is AZD6738, M4344, or M6620.
  • the weel inhibitor is AZDI 775.
  • the second therapeutic agent is an epigenetic drug.
  • epigenetic drug refers to a therapeutic agent that targets an epigenetic regulator.
  • epigenetic regulators include the histone lysine methyltransferases, histone arginine methyl transferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases.
  • Histone deacetylase inhibitors include, but are not limited to, vorinostat.
  • chemotherapeutic agents or other anti -proliferative agents can be combined with islatravir to treat proliferative diseases and cancer.
  • therapies and anticancer agents that can be used in combination with islatravir include surgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), endocrine therapy, a biologic response modifier (e.g., an interferon, an interleukin, tumor necrosis factor (TNF), hyperthermia and cryotherapy, an agent to attenuate any adverse effect (e.g., an antiemetic), and any other approved chemotherapeutic drug.
  • radiotherapy e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes
  • endocrine therapy e.g., a biologic response modifier (e.g.,
  • antiproliferative compounds include, but are not limited to, an aromatase inhibitor; an anti -estrogen, an anti -androgen; a gonadorelin agonist; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active agent; an alkylating agent; a retinoid, a carontenoid, or a tocopherol; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; an antimetabolite; a platin compound; a methionine aminopeptidase inhibitor; a bisphosphonate; an antiproliferative antibody; a heparanase inhibitor; an inhibitor of Ras oncogenic isoforms; a telomerase inhibitor; a proteasome inhibitor; a compound used in the treatment of hematologic malignancies; a Flt-3 inhibitor; an Hsp90 inhibitor; a kinesin spindle protein inhibitor
  • Nonlimiting exemplary' aromatase inhibitors include, but are not limited to, steroids, such as atamestane, exemestane, and formestane, and non-steroids, such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.
  • steroids such as atamestane, exemestane, and formestane
  • non-steroids such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.
  • Nonlimiting anti -estrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride.
  • Anti-androgens include, but are not limited to, bicalutamide.
  • Gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.
  • topoisomerase I inhibitors include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148.
  • Topoisomerase 11 inhibitors include, but are not limited to, anthracyclines, such as doxorubicin, daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones, such as mitoxantrone and losoxantrone; and podophillotoxines, such as etoposide and teniposide.
  • Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and microtubulin polymerization inhibitors including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof.
  • taxanes such as paclitaxel and docetaxel
  • vinca alkaloids such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine
  • discodermolides such as cochicine and epothilones and derivatives thereof.
  • Exemplary nonlimiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas, such as carmustine and lomustine.
  • Exemplary' nonlimiting cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib, rofecoxib, etoricoxib, valdecoxib, or a 5-alkyl-2-arylaminophenyl acetic acid, such as lumiracoxib.
  • MMP inhibitors include collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B, and AAJ996.
  • Exemplary nonlimiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and possess antiproliferative activity such as sirolimus, everolimus, CCI-779, and ABT578.
  • mTOR mammalian target of rapamycin
  • Exemplary' nonlimiting antimetabolites include 5-fluorouraci I (5-FU), capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists, such as pemetrexed.
  • Exemplary' nonlimiting platin compounds include carboplatin, cis-platin, cisplatinum, and oxaliplatin.
  • Exemplary nonlimiting methionine aminopeptidase inhibitors include bengamide or a derivative thereof and PPI-2458.
  • Exemplary nonlimiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.
  • antiproliferative antibodies include trastuzumab, trastuzumab-DMl, cetuximab, bevacizumab, rituximab, PR064553, and 2C4.
  • antibody is meant to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.
  • Exemplary nonlimiting heparanase inhibitors include compounds that target, decrease, or inhibit heparin sulfate degradation, such as PI-88 and OGT2115.
  • an inhibitor of Ras oncogenic isoforms such as H ⁇ Ras, K-Ras, or N- Ras, as used herein refers to a compound which targets, decreases, or inhibits the oncogenic activity of Ras, for example, a farnesyl transferase inhibitor, such as L-744832, DK8G557, tipifarnib, and lonafarnib.
  • telomerase inhibitors include compounds that target, decrease, or inhibit the activity of telomerase, such as compounds that inhibit the telomerase receptor, such as telomestatin.
  • telomestatin compounds that inhibit the telomerase receptor
  • proteasome inhibitors include compounds that target, decrease, or inhibit the activity of the proteasome including, but not limited to, bortezomid.
  • FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, I- ⁇ -D-arabinofuransylcytosine (ara-c), and bisulfan; and ALK inhibitors, which are compounds which target, decrease, or inhibit anaplastic lymphoma kinase.
  • Exemplary nonlimiting Fit-3 inhibitors include PKC412, midostaurin, a staurosporine derivative, SU11248, and MLN518.
  • Exemplary nonlimiting HSP90 inhibitors include compounds targeting, decreasing, or inhibiting the intrinsic ATPase activity of HSP90; or degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17- allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds, radicicol and HDAC inhibitors.
  • a compound targeting/decreasing a protein or lipid kinase activity'; or a protein or lipid phosphatase activity; or any further anti -angiogenic compound includes a protein tyrosine kinase and/or serine and/or threonine kinase inhibitor or lipid kinase inhibitor, such as a) a compound targeting, decreasing, or inhibiting the activity of the platelet- deri ved growth factor-receptors (PDGFR), such as a compound that targets, decreases, or inhibits the activity of PDGFR, such as an N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SUIOI, SU6668, and GFB-111 , b) a compound targeting, decreasing, or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) a compound targeting, decreasing, or inhibiting the activity of the insulin-
  • PDGFR platelet- deri
  • Bcr- Abl kinase and mutants, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or dasatinib; j) a compound targeting, decreasing, or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK family members, and/or members of the cyclin-dependent kinase family (CDK), such as a staurosporine derivative disclosed in U.S.
  • PKC protein kinase C
  • Raf family of serine/threonine kinases members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK family members,
  • Patent No. 5,093,330 such as midostaurin
  • examples of further compounds include UCN- 01, safingoi, BAY 43-9006, bryostatin 1, perifosine, ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; a isochinoline compound; a farnesyl transferase inhibitor; PD184352 or QAN697, or .AT7519; k) a compound targeting, decreasing or inhibiting the activity of a protein-tyrosine kinase, such as imatinib mesylate or a tyrphostin, such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213, Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494
  • Exemplary compounds that target, decrease, or inhibit the activity of a protein or lipid phosphatase include inhibitors of phosphatase 1, phosphatase 2 A, or CDC25, such as okadaic acid or a derivative thereof.
  • Further anti-angiogenic compounds include compounds having another mechanism for their activity unrelated to protein or lipid kinase inhibition, e.g., thalidomide and TNP- 470.
  • Additional, nonlimiting, exemplary chemotherapeutic compounds include: daunorubicin, adriamycin, Ara- C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, PKC412, 6- mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6- thioguanine, cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxy-1H- isoindole-1, 3-dione derivatives, l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino)-4-(4- pyridylmethyl)phthalazine succinate, angiostatin, end
  • second therapeutic agents include, but are not limited to: a treatment for Alzheimer's Disease, such as donepezil and rivastigmine, a treatment for Parkinson's Disease, such as L- DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g., AVONEX® and REBIF®), glatiramer acetate, and mitoxantrone; a treatment for asthma, such as albuterol and montelukast; an agent for treating schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; an anti-inflammatory agent, such as a corticosteroid, a TNF blocker, IL-1 RA, aza
  • the second therapeutically active agent is an immune checkpoint inhibitor.
  • immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, cd47 inhibitors, and B7-H1 inhibitors.
  • islatravir is administered in combination with an immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, and a cd47 inhibitor,
  • the immune checkpoint inhibitor is a programmed cell death (PD-1) inhibitor.
  • PD-1 is a T-cell coinhibitory receptor that plays a pivotal role in the ability of tumor cells to evade the host's immune system. Blockage of interactions between PD-1 and PD-LI, a ligand of PD-1, enhances immune function and mediates antitumor activity.
  • PD-1 inhibitors include antibodies that specifically bind to PD-1. Particular anti-PD-1 antibodies include, but are not limited to nivolumab, pembrolizumab, STI-A1014, and pidilzumab.
  • the immune checkpoint inhibitor is a PD-LI (also known as B7-H1 or CD274) inhibitor.
  • PD-LI inhibitors include antibodies that specifically bind to PD-LI.
  • Particular anti-PD-L1 antibodies include, but are not limited to, avelumab, atezolizumab, durvalumab, and BMS-936559.
  • the immune checkpoint inhibitor is a CTLA-4 inhibitor.
  • CTLA-4 also known as cytotoxic T-lymphocyte antigen 4
  • CTLA-4 is a protein receptor that downregulates the immune system.
  • CTLA-4 is characterized as a "brake” that binds costimulatory molecules on antigen-presenting cells, which prevents interaction with CD28 on T cells and also generates an overtly inhibitory signal that constrains T cell activation.
  • CTLA-4 inhibitors include antibodies that specifically bind to CTLA-4.
  • Particular anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab.
  • the immune checkpoint inhibitor is a LAG3 inhibitor.
  • LAG3, Lymphocyte Activation Gene 3 is a negative co-simulatory receptor that modulates T cell homeostatis, proliferation, and activation.
  • LAG3 has been reported to participate in regulatory T cells (Tregs) suppressive function. A large proportion of LAG3 molecules are retained in the cell close to the microtubule-organizing center, and only induced following antigen specific T cell activation.
  • Regs regulatory T cells
  • Examples of LAG3 inhibitors include antibodies that specifically bind to LAG3. Particular anti-LAG3 antibodies include, but are not limited to, GSK2831781.
  • the immune checkpoint inhibitor is a TIM3 inhibitor.
  • TIM3, T-cell immunoglobulin and mucin domain 3 is an immune checkpoint receptor that, functions to limit the duration and magnitude of T H 1 and T C 1 T-cell responses.
  • the TIM3 pathway is considered a target for anticancer immunotherapy due to its expression on dysfunctional CD8 + T cells and Tregs, which are two reported immune cell populations that constitute immunosuppression in tumor tissue. Anderson, Cancer Immunology’ Research 2:393-98 (2014).
  • Examples of TIM3 inhibitors include antibodies that specifically bind to TIM3.
  • the immune checkpoint inhibitor is a cd47 inhibitor. See Unanue, E.R., PNAS 110: 10886-87 (2013).
  • antibody is meant to include intact monoclonal antibodies, polyclonal antibodies, multi specific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.
  • antibody is meant to include soluble receptors that do not possess the Fc portion of the antibody.
  • the antibodies are humanized monoclonal antibodies and fragments thereof made by means of recombinant genetic engineering.
  • Another class of immune checkpoint inhibitors include polypeptides that bind to and block PD-1 receptors on T-cells without triggering inhibitor signal transduction.
  • Such peptides include B7-DC polypeptides, B7-H1 polypeptides, B7-1 polypeptides and B7-2 polypeptides, and soluble fragments thereof, as disclosed in U.S. Pat. 8,114,845.
  • Another class of immune checkpoint inhibitors include compounds with peptide moieties that inhibit PD-1 signaling. Examples of such compounds are disclosed in U.S. Pat. 8,907,053.
  • Another class of immune checkpoint inhibitors include inhibitors of certain metabolic enzymes, such as indoleamine 2,3 dioxygenase (IDO), which is expressed by infiltrating myeloid cells and tumor cells.
  • IDO indoleamine 2,3 dioxygenase
  • the 11)0 enzyme inhibits immune responses by depleting amino acids that are necessary for anabolic functions in T cells or through the synthesis of particular natural ligands for cytosolic receptors that are able to alter lymphocyte functions.
  • IDO blocking agents include, but are not limited to levo- 1 -methyl typtophan (L-1MT) and 1 -methyl -tryptophan (1MT).
  • the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, STI-Al l 10, avelumab, atezolizumab, durvalumab, STI-A1014, ipilimumab, tremelimumab, GSK2831781, BMS-936559 or MED14736.
  • the RTI when the RTI is an FDA approved drug, the RTI may be administered in therapeutically effective amounts that are approved for therapeutic use.
  • the amounts effective can be determined with no more than routine experimentation. For example, amounts effective may range from about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg.
  • the dosage of a composition can be at any dosage including, but not limited to, about 1 ⁇ g/kg.
  • the dosage of a composition may be at any dosage including, but not limited to, about 1 ⁇ g/kg, about 10 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ⁇ g/kg, about 150 ⁇ g/kg, about 175 ⁇ g/kg, about 200 ⁇ g/kg, about 225 ⁇ g/kg, about 250 ⁇ g/kg, about 275 ⁇ g/kg, about 300 ⁇ g/kg, about 325 , ⁇ g/kg, about 350 ⁇ g/kg, about 375 ⁇ g/kg, about 400 ⁇ g/kg, about 425 ⁇ g/kg, about 450 ⁇ g/kg, about 475 ⁇ g/kg, about 500 ⁇ g/kg, about 525 ⁇ g/kg, about 550 ⁇ g/kg, about 575 ⁇ g/kg, about 600 ⁇ g/kg, about 625 ⁇ g/kg, about 650 ⁇
  • the dosage is 1 mg-500 mg. In some embodiments, the dosage is 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 mg. These doses may be unitary or divided and may be administered one or more times per day. The above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure. In practice, the physician determines therapeutically effective amounts and the actual dosing regimen that is most suitable for an individual subject, which can vary with the age, weight, and response of the particular subject.
  • the RTI may be administered once, twice or three times per day for 1 day to the end of life, or for 1 day to 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more years, or until the RTI causes unacceptable side effects or is no longer useful.
  • the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afmitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capeci tabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Peijeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemacic
  • the at least one second therapeutic agent is Xeloda® (capecitabine), Eloxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta-lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy® (ipilmum
  • the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfmizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
  • Etopophos® etoposide
  • Hycamtin® topotecan
  • VePesid® etoposide
  • Toposar® etoposide
  • Opdivo® nivolumab
  • Keytruda® pembrolizumab
  • Tecentriq® atezolizum
  • the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
  • Gemzar® Gamcitabine
  • fluorouracil Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (
  • the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
  • the at least one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vanias® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi ® (enzal utami de) .
  • the at least one second therapeutic agent is a STING agonist.
  • STING agonists include E7766, MIW815, SNX281, and TAK-676. See, e.g., Aval et al., Journal of Clinical Medicine 9:3323 (2020); Su et al., Theranostics 9:7759- 7771 (2019).
  • the RTI and/or DDR enzyme inhibitor and at least one second therapeutic agent may be administered separately or together as part of a unitary pharmaceutical composition.
  • the patient is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
  • patient and “subject” as used herein are synonymous terms referring to any human or animal that is in need of or might benefit from administration of a RTI and/or DDR enzyme inhibitor for treating cancer.
  • mammals e.g., humans, although the methods and compositions provided herein are not intended to be so limited.
  • Other subjects include veterinary animals, e.g., cows, sheep, pigs, horses, dogs, cats and the like.
  • the subject is a human.
  • the subject is an animal.
  • the methods of the present disclosure can be accomplished by administering RTI as the neat compound or as a pharmaceutical composition.
  • Administration of a pharmaceutical composition, or a neat RTI and/or DDR enzyme inhibitor can be performed before, during, or after the clinical diagnosis of the cancer.
  • the pharmaceutical compositions are sterile, and contain no toxic, carcinogenic, or mutagenic compounds that would cause an adverse reaction when administered.
  • kits comprising the RTI and/or DDR enzyme inhibitor and, optionally, at least one second therapeutic agent useful for the treatment of cancer associated, packaged separately or together, and an insert having instructions for using these active agents.
  • the RTI and/or DDR enzyme inhibitor is packaged alone together with instructions to administered together with the at least one second therapeutic agent.
  • the RTI and/or DDR enzyme inhibitor and the at least one second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect.
  • the RTI and the at least one second therapeutic agent can be administered from a single composition or two separate compositions.
  • the second therapeutic agent is administered in an amount to provide its desired therapeutic effect.
  • the effective dosage range for each optional therapeutic agent is known in the art, and the optional therapeutic agent is administered to an individual in need thereof within such established ranges.
  • the present disclosure encompasses the preparation and use of salts of a RTI and/or DDR enzyme inhibitor.
  • a "pharmaceutically acceptable salt” refers to salts or zwitterionic forms of a RTI and/or DDR enzyme inhibitor. Salts of a RTI and/or DDR enzyme inhibitor can be prepared during the final isolation and purification of the compound or separately by reacting the compound with a suitable acid.
  • the pharmaceutically acceptable salts of a RTI and/or DDR enzyme inhibitor can be acid addition salts formed with pharmaceutically acceptable acids.
  • acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Non-limiting examples of salts of a RTI and/or DDR enzyme inhibitor include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerol phsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesityl enesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulf
  • solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents.
  • solvate as used herein is a combination, physical association and/or solvation of a compound with a solvent molecule such as, e.g. a - disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound is about 2: 1, about 1 : 1 or about 1 :2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding.
  • solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • solvate encompasses both solution- phase and isolatable solvates.
  • a RTI and/or DDR enzyme inhibitor can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol. It is intended that the disclosure includes both solvated and unsolvated forms of a RTI.
  • solvate is a hydrate.
  • a "hydrate” relates to a particular subgroup of solvates where the solvent molecule is water.
  • Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M.
  • a typical, non-limiting, process of preparing a solvate would involve dissolving a RTI in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration.
  • Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvate in a cry sial of the solvate.
  • the RTI and/or DDR enzyme inhibitor is typically are administered in admixture with a pharmaceutical carrier to give a pharmaceutical composition selected with regard to the intended route of administration and standard pharmaceutical practice.
  • Pharmaceutical compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the RTI and/or DDR enzyme inhibitor.
  • compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen.
  • a therapeutically effective amount of a RTI and/or DDR enzyme inhibitor is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir.
  • the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant.
  • the tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a RTI and/or DDR enzyme inhibitor, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof.
  • a liquid carrier such as water, petroleum, or oils of animal or plant origin, can be added.
  • the liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols.
  • the composition contains about 0.1 % to about 90%, and preferably about 1% to about 50%, by weight, of a RTI and/or DDR enzyme inhibitor.
  • composition When a therapeutically effective amount of a RTI and/or DDR enzyme inhibitor is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution.
  • parenterally acceptable solutions having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.
  • a preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.
  • a RTI and/or DDR enzyme inhibitor can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained by adding a RTI and/or DDR enzyme inhibitor to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.
  • a RTI and/or DDR enzyme inhibitor can be formulated for parenteral administration by injection, e.g,, by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the RTI and/or DDR enzyme inhibitor in water-soluble form.
  • suspensions of a compound of a RTI can be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.
  • the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions.
  • a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a RTI and/or DDR enzyme inhibitor can be administered orally in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • excipients such as starch or lactose
  • capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents.
  • a RTI and/or DDR enzyme inhibitor also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily.
  • a RTI and/or DDR enzyme inhibitor typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
  • biomarker refers to any biological compound, such as a gene, a protein, a fragment of a protein, a peptide, a polypeptide, a nucleic acid, etc., or chromosome abnormality, such as a chromosome translocation, that can be detected and/or quantified in a subject in vivo or in a biological sample obtained from a subject.
  • a biomarker can be the entire intact molecule, or it can be a portion or fragment thereof.
  • the expression level of the biomarker is measured.
  • the expression level of the biomarker can be measured, for example, by detecting the protein or RNA, e.g., mRNA, level of the biomarker.
  • portions or fragments of biomarkers can be detected or measured, for example, by an antibody or other specific binding agent.
  • a measurable aspect of the biomarker is associated with a given state of the subject, such as the subject's age.
  • measurable aspects may include, for example, the presence, absence, or concentration, i.e., expression level, of the biomarker in the subject, or biological sample obtained from the subject.
  • measurable aspects may include, for example, allelic versions of the biomarker or type, rate, and/or degree of mutation of the biomarker, also referred to herein as mutation status.
  • biomarkers that are detected based on expression level of protein or RNA expression level measured between different phenotypic statuses can be considered different, for example, if the mean or median expression level of the biomarker in the different groups is calculated to be statistically significant. Common tests for statistical significance include, among others, t-test, ANOVA, Kruskal -Wall is, Wilcoxon, Mann- Whitney, Significance Analysis of Microarrays, odds ratio, etc.
  • Biomarkers, alone or in combination provide measures of relative likelihood that a subject belongs to one phenotypic status or another. Therefore, they are useful, inter alia, as markers for disease and as indicators that particular therapeutic treatment regimens will likely result in beneficial patient outcomes.
  • overexpression indicates that the expression level of the biomarker in the subject having a disease, condition, or disorder is amplified, e.g., above the mean or median expression level of the biomarker in, e.g., a normal undiseased subject.
  • Biomarkers include, but are not limited to, DDR enzymes, e.g., Pol ⁇ Pol ⁇ , or Pol ⁇ , or genes, e.g., POLE, POLM, or POLQ.
  • the measurable aspect of the biomarker is its expression status.
  • the measurable aspect of the biomarker is elevated levels, e.g., over express! on, of the biomarker.
  • the measurable aspect of the biomarker is its mutation status.
  • the biomarker is Pol ⁇ expression which is differentially present in a subject of one phenotypic status, e.g., a subject having cancer as compared with another phenotypic status, e.g., a normal undiseased subject or a subject having a cancer without overexpression of Pol ⁇ .
  • the biomarker is overexpression of Pol ⁇ in cancer cells.
  • the biomarker is Pol ⁇ expression which is differentially present in a subject of one phenotypic status, as compared with another phenotypic status.
  • the biomarker is overexpression of Pol ⁇ , e.g., in cancer cells.
  • the biomarker is overexpression of POLE, e.g., in cancer cells.
  • the biomarker is Pol ⁇ expression which is differentially present in a subject of one phenotypic status as compared with another phenotypic status.
  • the biomarker is overexpression of Pol ⁇ , e.g., in cancer cells.
  • the biomarker is overexpression of POLM, e.g., in cancer cells.
  • the biomarker is BR.CA1 expression which is differentially present in a subject of one phenotypic status, e.g., a subject having cancer as compared with another phenotypic status, e.g., a normal undiseased subject or a subject having a cancer without overexpression of BRCA1 .
  • the biomarker is overexpression of BRCA1 in cancer cells.
  • the biomarker is BRCA2 expression which is differentially present in a subject of one phenotypic status, e.g., a subject having cancer as compared with another phenotypic status, e.g., a normal undiseased subject or a subject having a cancer without overexpression of BRCA2.
  • the biomarker is overexpression of BRCAl in cancer cells.
  • the biomarker is Pol ⁇ , Pol ⁇ or Pol ⁇ expression which is differentially present in a subject of one phenotypic status, e.g., a subject after administration of a Compound of the Disclosure, as compared with another phenotypic status, e.g., a normal undiseased subject or a subject before administration of a Compound of the Disclosure.
  • the biomarker is descressed expression of Pol ⁇ , Pol ⁇ , or Pol ⁇ caused by administration of a Compound of the Disclosure to a subject.
  • Biomarker standards can be predetermined, determined concurrently, or determined after a biological sample is obtained from the subject.
  • Biomarker standards for use with the methods described herein can, for example, include data from samples from subjects without cancer and/or data from samples from subjects with a cancer. Comparisons can be made to establish predetermined threshold biomarker standards for different classes of subjects, e.g., diseased vs. non-diseased subjects. The standards can be run in the same assay or can be known standards from a previous assay.
  • a biomarker is differentially present between different phenotypic status groups if the mean or median expression or mutation levels of the biomarker is calculated to be different, i.e., higher or lower, between the groups.
  • biomarkers provide an indication that a subject, e.g., a subject having cancer, belongs to one phenotypic status or another.
  • biomarker in addition to individual biological compounds, e.g., Pol ⁇ , the term “biomarker” as used herein is meant to include groups, sets, or arrays of multiple biological compounds.
  • biomarker may comprise one, two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty, twenty five, thirty, or more, biological compounds.
  • the biomarker comprises one, two, or three biological compounds.
  • the determination of the expression level or mutation status of a biomarker in a subject can be performed using any of the many methods known in the art. Any method known in the art for quantitating specific proteins and/or detecting biomarker expression, e.g., Pol ⁇ , Pol ⁇ , or Pol ⁇ expression, and/or or the expression or mutation levels of any other biomarker(s) in a patient or a biological sample may be used in the methods of the disclosure. Examples include, but are not limited to, PCR (polymerase chain reaction), or RT-PCR, flow cytometry.
  • RNA expression e.g., ELISA (enzyme linked immunosorbent assay), RIA (radioimmunoassay), Simoa TM , gene chip analysis of RNA expression, immunohistochemistry, immunofluorescence, or massspectroscopy.
  • ELISA enzyme linked immunosorbent assay
  • RIA radioimmunoassay
  • Simoa TM gene chip analysis of RNA expression, immunohistochemistry, immunofluorescence, or massspectroscopy.
  • Certain embodiments of the disclosure include methods wherein biomarker RNA expression (transcription) is determined.
  • Other embodiments of the disclosure include methods wherein protein expression in the biological sample is determined.
  • a biological sample is obtained from the subject and the biological sample is assayed for determination of a biomarker expression or mutation status.
  • the biological sample is blood from the subject.
  • the biological sampl e is the cancer tissue or cells of the patient,
  • Northern blot analysis of biomarker transcription in a tumor cell sample is performed.
  • Northern analysis is a standard method for detection and/or quantitation of mRNA levels in a sample. Initially, RNA is isolated from a sample to be assayed using Northern biot analysis, In the analysis, the RNA samples are first separated by size via electrophoresis in an agarose gel under denaturing conditions. The RNA is then transferred to a membrane, crosslinked and hybridized with a labeled probe. Typically, Northern hybridization involves polymerizing radiolabeled or nonisotopically labeled DNA, in vitro, or generation of oligonucleotides as hybridization probes.
  • the membrane holding the RNA sample is prehybridized or blocked prior to probe hybridization to prevent the probe from coating the membrane and, thus, to reduce non-specific background signal.
  • unhybridized probe is removed by washing in several changes of buffer. Stringency of the wash and hybridization conditions can be designed, selected and implemented by any practitioner of ordinary skill in the art. Detection is accomplished using detectably labeled probes and a suitable detection method. Radiolabeled and non-radiolabled probes and their use are well known in the art. The presence and or relative levels of expression of the biomarker being assayed can be quantified using, for example, densitometry.
  • biomarker expression and/or mutation status is determined using RT-PCR.
  • RT-PCR allows detection of the progress of a PCR amplification of a target gene in real time. Design of the primers and probes required to detect expression and/or mutation status of a biomarker of the disclosure is within the skill of a practitioner of ordinary skill in the art..
  • RT-PCR can be used, for example, to determine the level of RNA encoding a biomarker of the disclosure in a tissue sample.
  • RNA from the biological sample is isolated, under RNAse free conditions, than converted to DNA by treatment with reverse transcriptase. Methods for reverse transcriptase conversion of RNA to DNA are well known in the art..
  • RT-PCR probes depend on the 5'-3‘ nuclease activity of the DNA polymerase used for PCR to hydrolyze an oligonucleotide that is hybridized to the target amplicon (biomarker gene).
  • RT-PCR probes are oligonucleotides that have a fluorescent reporter dye attached to the 5' end and a quencher moiety coupled to the 3' end (or vice versa). These probes are designed to hybridize to an internal region of a PCR product. In the unhybridized state, the proximity of the fluor and the quench molecules prevents the detection of fluorescent signal from the probe.
  • a western blot is a method for protein detection in a given sample of tissue homogenate or extract. It uses gel electrophoresis to separate denatured proteins by mass. The proteins are then transferred out of the gel and onto a membrane (e.g., nitrocellulose or poly vinylidene fluoride (PVDF)), where they are detected using a primary antibody that specifically bind to the protein. The bound antibody can then detected by a secondary' antibody that is conjugated with a detectable label (e.g., biotin, horseradish peroxidase or alkaline phosphatase). Detection of the secondary label signal indicates the presence of the protein.
  • a detectable label e.g., biotin, horseradish peroxidase or alkaline phosphatase.
  • the expression of a protein encoded by a biomarker is detected by enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • "sandwich ELISA” comprises coating a plate with a capture antibody; adding sample wherein any antigen present binds to the capture antibody; adding a detecting antibody which also binds the antigen, adding an enzyme-linked secondary antibody which binds to detecting antibody; and adding substrate which is converted by an enzyme on the secondary antibody to a detectable form. Detection of the signal from the secondary antibody indicates presence of the biomarker antigen protein.
  • present disclosure provides methods of treating a subject having cancer, the method comprising: (a) determining whether a biomarker, e.g., overexpression of Pol ⁇ , Pol ⁇ , or Pol ⁇ , is present or absent in a biological sample taken from the subject; and (b) administering an RTI and/or DDR enzyme inhibitor to the subject if the biomarker is present in the biological sample.
  • a biomarker e.g., overexpression of Pol ⁇ , Pol ⁇ , or Pol ⁇
  • the present disclosure provides a method of identifying whether a subject having cancer as a candidate for treatment with a RTI and/or DDR enzyme inhibitor, the method comprising: (a) determining whether a biomarker, e.g.. overexpression of POLQ, is present or absent in a biological sample taken from the subject; and (b) identifying the subject as being a candidate for treatment if the biomarker is present; or (c) identifying the subject as not being a candidate for treatment if the biomarker is absent.
  • a biomarker e.g.. overexpression of POLQ
  • the present disclosure provides a method of predicting treatment outcome in a subject having cancer, the method comprising determining whether a bi ⁇ marker, e.g., overexpression of Pol ⁇ , Pol rp or Pol ⁇ , is present or absent in a biological sample taken from the subject, wherein (a) the presence of the biomarker in the biological sample indicates that administering a RTI and/or DDR enzyme inhibitor to the subject will likely cause a favorable therapeutic response; and (b) the absence of the biomarker in the biological sample indicates that administering a RTI and/or DDR enzyme inhibitor to the subject will likely cause an unfavorable therapeutic response.
  • a bi ⁇ marker e.g., overexpression of Pol ⁇ , Pol rp or Pol ⁇
  • the present disclosure provides a method, comprising administering a therapeutically effective amount of a RTI and/or DDR enzyme inhibitor to a subject in need thereof, wherein: (a) the subject has cancer; and (b) the cancer is characterized as having a biomarker, e.g., overexpression of one or more DNA damage repair enzymes, e.g., overexpression of Pol 6, Pol ⁇ , or Pol ⁇ .
  • a biomarker e.g., overexpression of one or more DNA damage repair enzymes, e.g., overexpression of Pol 6, Pol ⁇ , or Pol ⁇ .
  • the present disclosure provides a method of treating a subject having cancer, the method comprising:
  • the present disclosure provides a method of identifying whether a subject having cancer as a candidate for treatment with a Compound of the Disclosure, the method comprising:
  • the present disclosure provides a method of predicting treatment outcome in a subject having cancer, the method comprising determining whether an overexpression of one or more DNA damage repair enzymes, e.g., Pol ⁇ , Pol ⁇ , and/or Pol ⁇ , is present or absent in a biological sample taken from the subject, wherein:
  • the present disclosure provides a Compound of the Disclosure for use in treating a subject having cancer, wherein;
  • a biomarker e.g., one or more DNA damage repair enzymes, e.g., Pol 6, Pol ⁇ , and/or Pol ⁇ , in a biological sample taken from the subject is determined; and
  • the present disclosure provides the use of a Compound of the Disclosure in the manufacture of a medicament for treating a subject having cancer, wherein:
  • a biomarker e.g., one or more DNA damage repair enzymes, e.g., Pol ⁇ , Pol ⁇ and/or Pol ⁇
  • a biomarker e.g., one or more DNA damage repair enzymes, e.g., Pol ⁇ , Pol ⁇ and/or Pol ⁇
  • A DNA damage repair enzyme inhibitors for treating cancer.
  • Embodiment 1 A method for treating cancer in subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Table 3 to the subject.
  • Embodiment 2 The method of Embodiment 1, wherein the compound of Table 3 is 2-amino-9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-
  • Embodiment 3 The method of Embodiment 1, wherein the compound of Table 3 is (2R,3 S,5R)-5-(4-amino-2-oxopyrimidin- 1 (2H)-yl)-3-hydroxy-2-
  • Embodiment 4 The method of Embodiment 1, wherein the compound of Table 3 is (2R,3S,5R)-5-(2,6-diamino-9H-purin-9-yl)-2-(hydroxymethyl)-2- vinyltetrahydrofuran-3-ol; (2R,3S,5R)-5-(2,6-di amino- 9H-purin-9-yl)-2-ethyl-2-
  • Embodiment 5 The method of any one of Embodiments 1-4, wh erein the cancer is breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, ovarian cancer, or head and neck cancer.
  • Embodiment 6 The method of Embodiment 5, wherein the cancer is breast cancer.
  • Embodiment 7 The method of Embodiment 5, wherein the cancer is colon cancer.
  • Embodiment 8 The method of Embodiment 5, wherein the cancer is lung cancer.
  • Embodiment 9 The method of Embodiment 5, wherein the cancer is pancreatic ductal cancer.
  • Embodiment 10 The method of Embodiment 5, wherein the cancer is prostate cancer.
  • Embodiment 11 The method of Embodiment 5, wherein the prostate cancer is high-risk localized prostate cancer.
  • Embodiment 12 The method of Embodiment 5, wherein the cancer is ovarian cancer.
  • Embodiment 13 The method of Embodiment 5, wherein the cancer is head and neck cancer.
  • Embodiment 14 The method of any one of Embodiments 1-5, wherein the subject has prostate cancer and the compound of Table 3 is administered as an adjuvant therapy.
  • Embodiment 15 The method of any one of Embodiments 1-5, wherein the subject has prostate cancer and the compound of Table 3 is administered as a neoadjuvant therapy.
  • Embodiment 16 The method of any one of Embodiments 1-15 further comprising administering a therapeutically effective amount of at least one second therapeutic agent useful for treating the cancer.
  • Embodiment 17 The method of Embodiment 16, wherein the cancer is breast cancer and the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afinitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemaciclib),
  • Embodiment 18 The method of Embodiment 16, wherein the cancer is colon cancer and the at least one second therapeutic agent is Xeloda® (capeci tabine), El oxatin® (oxaliplatin), fluorouracil, A vastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta- lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy®
  • Embodiment 19 The method of Embodiment 16, wherein the cancer is lung cancer and the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfinizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
  • Etopophos® etoposide
  • Hycamtin® topotecan
  • VePesid® etoposide
  • Toposar® etoposide
  • Opdivo® nivolumab
  • Embodiment 20 The method of Embodiment 16, wherein the cancer is pancreatic ductal cancer and the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
  • Gemzar® Gamcitabine
  • fluorouracil Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar
  • Embodiment 21 The method of Embodiment 16, wherein the cancer is head and neck cancer and the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
  • Erbituz® cetuximab
  • Taxotere® docetaxel
  • Trexall® metalhotrexate
  • Keytruda® pembrolizumab
  • Opdivo® nivolumab
  • Embodiment 22 The method of Embodiment 16, wherein the cancer is prostate cancer and the at least one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
  • Suprefact® buserelin
  • Firmagon® degarelix
  • Zoladex® goserelin
  • Vantas® histrelin
  • Eligard® leuprolide
  • Orgovyx® relugolix
  • Trelstar® triptorelin
  • Embodiment 23 The method of Embodiment 16, wherein the at least one second therapeutic agent is a STING agonist.
  • Embodiment 24 The method of any one of Embodiments 1-23, wherein the subject is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
  • Embodiment 25 A kit for carrying out the method of any one Embodiments 1-24, the kit comprising (i) a compound of Table 3; and (ii) and instructions for administering the compound of Table 3 to a subject having cancer.
  • Embodiment 26 The kit of Embodiment 25 further comprising at least one second therapeutic agent.
  • Embodiment 27 The method of any one of Embodiments 1-24, wherein the cells of the cancer are suspected to or exhibit deficiency of a DDR enzyme, e.g., one or more DDR enzymes of Table C, e.g., Pol ⁇ , Pol ⁇ , and/or Pol ⁇ , or the cells of the cancer are suspected to or exhibit amplification of a DDR gene, e.g., one or more DDR genes of Table C, e.g., POLE, POLM, and/or POLQ.
  • a DDR enzyme e.g., one or more DDR enzymes of Table C, e.g., Pol ⁇ , Pol ⁇ , and/or Pol ⁇
  • a DDR gene e.g., one or more DDR genes of Table C, e.g., POLE, POLM, and/or POLQ.
  • Embodiment 1 A compound of Table 3 for use in treating cancer in a subj ect.
  • Embodiment 2 The compound of Table 3 for use of Embodiment 1, wherein the compound of Table 3 is 2-amino-9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-1 ,9-dihydro-6H-purin-6-one; 4-amino-1-
  • Embodiment 3 The compound of Table 3 for use of Embodiment 1 , wherein the compound of Table 3 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxy- 2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile; 4-amino-1-((2R,4S,5R)-4-hydroxy ⁇ 5- (hydroxymethyl)-5-methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-one; or 4-amino-1- ((2R,4S,5R)-5-ethyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)- one.
  • Embodiment 4 The compound of Table 3 for use of Embodiment 1, wherein the compound of Table 3 is (2R,3S,5R)-5-(2,6-diamino-9H-purin-9-y
  • Embodiment 5 The compound of Table 3 for use of any one of Embodiments
  • cancer is breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, ovarian cancer, or head and neck cancer.
  • Embodiment 6 The compound of Table 3 for use of Embodiment 5, wherein the cancer is breast cancer.
  • Embodiment 7 The compound of Table 3 for use of Embodiment 5, wherein the cancer is colon cancer.
  • Embodiment 8 The compound of Table 3 for use of Embodiment 5, wherein the cancer is lung cancer.
  • Embodiment 9 The compound of Table 3 for use of Embodiment 5, wherein the cancer is pancreatic ductal cancer.
  • Embodiment 10 The compound of Table 3 for use of Embodiment 5, wherein the cancer is prostate cancer.
  • Embodiment 11 The compound of Table 3 for use of Embodiment 5, wherein the prostate cancer is high-risk localized prostate cancer.
  • Embodiment 12 The compound of Table 3 for use of Embodiment 5, wherein the cancer is ovarian cancer.
  • Embodiment. 13 The compound of "fable 3 for use of Embodiment 5, wherein the cancer is head and neck cancer.
  • Embodiment 14 The compound of Table 3 for use of any one of Embodiments
  • Embodiment 15 The compound of Table 3 for use of any one of Embodiments
  • Embodiment 16 The compound of Table 3 for use of any one of Embodiments
  • 1-15 further comprising administering a therapeutically effective amount of at least one second therapeutic agent useful for treating the cancer.
  • Embodiment 17 The compound of Table 3 for use of Embodiment 16, wherein the cancer is breast cancer and the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afinitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (a
  • Embodiment 18 The compound of Table 3 for use of Embodiment 16, wherein the cancer is colon cancer and the at least one second therapeutic agent is Xeloda® (capecitabine), Eloxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta-lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy
  • Embodiment 19 The compound of Table 3 for use of Embodiment 16, wherein the cancer is lung cancer and the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfinizi® (durvaiumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel.
  • Gemcitabine Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
  • Embodiment 20 The compound of Table 3 for use of Embodiment 16, wherein the cancer is pancreatic ductal cancer and the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
  • Gemzar® Gamcitabine
  • fluorouracil Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrex
  • Embodiment 21 The compound of Table 3 for use of Embodiment 16, wherein the cancer is head and neck cancer and the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
  • Erbituz® cetuximab
  • Taxotere® docetaxel
  • Trexall® metalhotrexate
  • Keytruda® pembrolizumab
  • Opdivo® nivolumab
  • Embodiment 22 The compound of Table 3 for use of Embodiment 16, wherein the cancer is prostate cancer and the at least one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
  • Suprefact® buserelin
  • Firmagon® degarelix
  • Zoladex® goserelin
  • Vantas® histrelin
  • Eligard® leuprolide
  • Orgovyx® relugolix
  • Trelstar® triptorelin
  • Embodiment 23 The compound of Table 3 for use of Embodiment 16, wherein the at least one second therapeutic agent is a STING agonist.
  • Embodiment 24 The compound of Table 3 for use of any one of Embodiments
  • the subject is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
  • Embodiment 25 The compound of Table 3 for use of any one of Embodiments 1-24, wherein the cells of the cancer are suspected to or exhibit deficiency of a DDR enzyme, e.g., one or more DDR enzymes of Table C, e.g., Pol q, Pol ⁇ , and/or Pol ⁇ , or the cells of the cancer are suspected to or exhibit amplification of a DDR gene, e.g., one or more DDR genes of Table C, e.g., POLH, POLM, and/or POLQ.
  • a DDR enzyme e.g., one or more DDR enzymes of Table C, e.g., Pol q, Pol ⁇ , and/or Pol ⁇
  • the cells of the cancer are suspected to or exhibit amplification of a DDR gene, e.g., one or more DDR genes of Table C, e.g., POLH, POLM, and/or POLQ.
  • C DNA damage
  • Embodiment 1 Use of a compound of Table 3 in the manufacture of a medicament for treating cancer in a subject.
  • Embodiment 2 The use of Embodiment 1, wherein the compound of Table 3 is 2-amino-9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl) ⁇ 1,9-dihydro-6H-purin-6-one; 4-amino-1-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-
  • Embodiment 3 The use of Embodiment 1 , wherein the compound of T able 3 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxy-2-
  • Embodiment 4 The use of Embodiment 1, wherein the compound of Table 3 is (2R,3S,5R)”5-(2,6-diamino-9H-purin-9-yl)”2-(hydroxymethyl)-2-vinyltetrahydrofuran- 3-ol; (2R,3S,5R)-5-(2,6-diamino-9H-purin-9-yl)-2-ethyl-2-
  • Embodiment 5 The use of any one of Embodiments 1-4, wherein the cancer is breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, ovarian cancer, or head and neck cancer.
  • Embodiment 6 The use of Embodiment 5, wherein the cancer is breast cancer.
  • Embodiment 7 The use of Embodiment 5, wherein the cancer is colon cancer.
  • Embodiment 8 The use of Embodiment 5, wherein the cancer is lung cancer.
  • Embodiment 9 The use of Embodiment 5, wherein the cancer is pancreatic ductal cancer.
  • Embodiment 10 The use of Embodiment 5, wherein the cancer is prostate cancer.
  • Embodiment 11 The use of Embodiment 5, wherein the prostate cancer is high-risk localized prostate cancer.
  • Embodiment 12 The use of Embodiment 5, wherein the cancer is ovarian cancer.
  • Embodiment 13 The use of Embodiment 5, wherein the cancer is head and neck cancer.
  • Embodiment 14 The use of any one of Embodiments 1-5, wherein the subject has prostate cancer and the compound of Table 3 is administered as an adjuvant therapy.
  • Embodiment 15 The use of any one of Embodiments 1-5, wherein the subject has prostate cancer and the compound of Table 3 is administered as a neoadjuvant therapy.
  • Embodiment 16 The use of any one of Embodiments 1-15 further comprising administering a therapeutically effective amount of at least one second therapeutic agent useful for treating the cancer.
  • Embodiment 17 The use of Embodiment 16, wherein the cancer is breast cancer and the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afmitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemaciclib), Verzen
  • Embodiment 18 The use of Embodiment 16, wherein the cancer is colon cancer and the at least one second therapeutic agent is Xeloda® (capecitabine), Eloxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipi racil/trifluri dine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta-lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy® (
  • Embodiment 19 The use of Embodiment 16, wherein the cancer is lung cancer and the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfmizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
  • Etopophos® etoposide
  • Hycamtin® topotecan
  • VePesid® etoposide
  • Toposar® etoposide
  • Opdivo® nivolumab
  • Embodiment 20 The use of Embodiment 16, wherein the cancer is pancreatic ductal cancer and the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
  • Gemzar® Gamcitabine
  • fluorouracil Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar
  • Embodiment 21 The use of Embodiment 16, wherein the cancer is head and neck cancer and the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
  • Erbituz® cetuximab
  • Taxotere® docetaxel
  • Trexall® metalhotrexate
  • Keytruda® pembrolizumab
  • Opdivo® nivolumab
  • Embodiment 22 The use of Embodiment 16, wherein the cancer is prostate cancer and the at least, one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
  • Embodiment 23 The use of Embodiment 16, wherein the at least one second therapeutic agent is a STING agonist.
  • Embodiment 24 The use of any one of Embodiments 1-23, wherein the subject is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
  • Embodiment 25 The use of any one of Embodiments 1-24, wherein the cells of the cancer are suspected to or exhibit deficiency of a DDR enzyme, e.g., one or more DDR enzymes of Table C, e.g., Pol ⁇ , Pol ⁇ , and/or Pol ⁇ , or the cells of the cancer are suspected to or exhibit amplification of a DDR gene, e.g., one or more DDR genes of Table
  • C e.g., POLII, POLM, and/or POLQ.
  • Embodiment 1 A method of treating cancer in a patient, wherein the cells of the cancer are suspected to or exhibit deficiency of a DNA repair enzyme, comprising administering to the patient an effective amount of a reverse transcriptase inhibitor (RTI) that is also a Pol ⁇ inhibitor, with the proviso that, the RTI is not ddC.
  • RTI reverse transcriptase inhibitor
  • Embodiment 2 The method of Embodiment 1, further comprising administering at least one second agent that is useful for the treatment of cancer.
  • Embodiment 3 The method of Embodiment 2, wherein the at least one second agent that is useful for the treatment of cancer is a poly ADP ribose polymerase
  • PARP PARP inhibitor
  • ATM inhibitor an ATM inhibitor
  • weel inhibitor an ATM inhibitor
  • ATR inhibitor an ATR inhibitor
  • Embodiment 4 The method of Embodiment 1, wherein the cells are resistant to PARP inhibition.
  • Embodiment 5 The method of Embodiment 2, wherein the second agent is a
  • Embodiment 6 The method of Embodiment 5, wherein the P AR P inhibitor is olaparib, rucaparib, niraparib or talazoparib.
  • Embodiment 7 The method of any one of Embodiments 1-6, wherein the DNA repair enzyme is encoded by at least one homologous recombination (HR) gene.
  • HR homologous recombination
  • Embodiment 8 The method of Embodiment 7, wherein the at least one HR gene is ATM, ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), FPEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4 LIG1, RPA1, BRI P l or PTEN.
  • the at least one HR gene is ATM, ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN),
  • Embodiment 9 The method of any one of Embodiments 1-8, wherein the RTI is lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alafenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV), 2',3'-dideoxyguanosine (ddG), 2’, 3 '-dideoxyadenosine (ddA), 2'-fluoro-2',3'- dideoxyarabinosyladenine (F-ddA), efavirenz (EFV), nevirapine (NVP), or abacavir (ABC), adefovir dipivoxil, telbivudine, or islatravir.
  • the RTI is lamivudine (3TC), zidovudine (AZT
  • Embodiment 10 The method of any one of Embodiments 1-8, wherein the RTI is any one or more of the compounds of Table A, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof.
  • Embodiment 11 The method of any one of Embodiments 1-8, wherein the RTI is any one or more of the compounds of Table B, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof.
  • Embodiment 12 The method of Embodiments 1-11, wherein the cancer is breast cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and/or BRCA2 genes.
  • Embodiment 13 The method of Embodiments 1-11, wherein the cancer is prostate cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and or BRCA2 genes.
  • Embodiment 14 The method of Embodiments 1-11, wherein the cancer is ovarian cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and /or BRCA2 genes.
  • Embodiment 15 The method of Embodiments 1-11, wherein the cancer is pancreatic cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and/or BRCA2 genes.
  • Embodiment 16 The method of any one of Embodiments 1-15, wherein the cells of the cancer exhibit overexpression of PolQ compared to the corresponding cells that are not cancer cells.
  • Embodiment 17 The method of any one of Embodiments 1-16, wherein the RTI inhibits human LINE- 1 retrotransposition with a half maximal inhibitory’ concentration of less than 100 nM in a HeLa cell-based dual-luciferase assay.
  • Embodiment 18 The method of any one of Embodiments 1-16, wherein the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitory concentration of less than 50 nM in a HeLa cell-based dual-luciferase assay.
  • Embodiment 19 The method of any one of Embodiments 1-16, wherein the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitory concentration of less than 10 nM in a HeLa cell-based dual-luciferase assay.
  • Embodiment 20 The method of Embodiment 2 for the treatment of breast cancer, wherein the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afinitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemacic
  • Embodiment 21 The method of Embodiment 2 for the treatment of colon cancer, wherein the at least one second therapeutic agent is Xeloda® (capecitabine), El oxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon betalb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy®
  • Embodiment 22 The method of Embodiment 2 for the treatment of lung cancer, wherein the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Itnfinizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
  • Etopophos® etoposide
  • Hycamtin® topotecan
  • VePesid® etoposide
  • Toposar® etoposide
  • Opdivo® nivolumab
  • Embodiment 23 The method of Embodiment 2 for the treatment of pancreatic ductal cancer, wherein the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afmitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
  • Gemzar® Gamcitabine
  • fluorouracil fluorouracil
  • Afmitor® everolimus
  • Tarceva® erlotinib
  • Abraxane® paclitaxel
  • capecitabine Sutent® (sunitinib)
  • Embodiment 24 The method of Embodiment 2 for the treatment of head and neck cancer, wherein the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
  • the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
  • Embodiment 25 The method of Embodiment 2 for the treatment of prostate cancer, wherein the at least one second therapeutic agent is Supr efact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (abiraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
  • Supr efact® buserelin
  • Firmagon® degarelix
  • Zoladex® goserelin
  • Vantas® histrelin
  • Eligard® leuprolide
  • Orgovyx® relugolix
  • Trelstar® tripto
  • Embodiment 26 The method of Embodiment 2, wherein the at least one second therapeutic agent is a STING agonist.
  • Embodiment 27 The method of any one of Embodiments 1-26, wherein the patient is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
  • Embodiment 28 The method of any one of Embodiments 1-27 wherein the
  • RTI is a nucleoside reverse transcriptase inhibitor (NRTI).
  • Embodiment 29 A kit for carrying out the method of any one Embodiments
  • kits comprising (i) a RTI; and (ii) and instructions for administering the RTI to a patient having cancer.
  • Embodiment 30 The kit of Embodiment 29, wherein the kit contains instructions for admini stering the RTI according to an intermittent dosing schedule.
  • Embodiment 31 The kit of Embodiment 29 or 30 further comprising at least one second therapeutic agent for the treatment of cancer.
  • Embodiment 32 The kit of Embodiment 29 or 30, further comprising instructions for administering the NRTI together with at least one second therapeutic agent for the treatment of cancer.
  • Step 1 O-((2R,3R,4S,5R)-2-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-4-
  • Step 2 N-(l-((2R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5- methyltetrahydroforan-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)benzamide.
  • Step 3 4-amino-1-((2R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5- methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-one.
  • Step 4 4-amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-5- methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-one (Cpd. No. 5).
  • a flame-dried round-bottomed flask equipped with a magnetic stirrer bar was charged with a solution of 4-amino-1- ((2R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5-methyltetrahydrofuran-2-yl)pyrimidin- 2(1H)-one (186 mg, 441 pmol) in MeOH (17.7 mL) under nitrogen atmosphere.

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Abstract

L'invention concerne un procédé de traitement du cancer par administration d'un inhibiteur d'enzyme de réparation de dommages (DDR) à un patient en ayant besoin dont les cellules cancéreuses sont suspectées ou ont une déficience d'une enzyme de réparation d'ADN.
PCT/US2023/016940 2022-03-30 2023-03-30 Procédé de traitement du cancer avec un inhibiteur d'enzyme de réparation de dommages à l'adn WO2023192505A2 (fr)

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AU2002241230B2 (en) * 2001-03-23 2007-11-29 Yeda Research And Development Co. Ltd. Methods and kits for determing a risk to develop cancer, for evaluating an effectiveness and dosage of cancer therapy and for correlating between an activity of a DNA repair enzyme and a cancer
MY184106A (en) * 2013-02-06 2021-03-18 Malaysian Palm Oil Board Treatment of dna damage and mitochondrial dysfunction using palm fruit juice
WO2016054055A1 (fr) * 2014-09-29 2016-04-07 Board Of Regent, The University Of Texas System Prédiction de la réponse aux inhibiteurs de parp et traitement combiné ciblant c-met et parp1
CA3110311A1 (fr) * 2018-08-24 2020-02-27 Biomedical Research Foundation Of The Academy Of Athens (Brfaa) Derives de 2,6-bis(((1h-benzo[d]imidazol-2-yl)thio)methyl)pyridine et de n2,n6-dibenzylpyridine-2,6-dicarboxamide et composes associes en tant qu'inhibiteurs de phosphoinositide 3 -kinase (pi3k) dans le traitement du cancer
EP4216963A1 (fr) * 2020-09-23 2023-08-02 Primefour Therapeutics, Inc. Procédé de traitement du cancer à l'aide d'un inhibiteur de la transcriptase inverse

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