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WO2025064750A1 - Polythérapie avec un inhibiteur de parg - Google Patents

Polythérapie avec un inhibiteur de parg Download PDF

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Publication number
WO2025064750A1
WO2025064750A1 PCT/US2024/047598 US2024047598W WO2025064750A1 WO 2025064750 A1 WO2025064750 A1 WO 2025064750A1 US 2024047598 W US2024047598 W US 2024047598W WO 2025064750 A1 WO2025064750 A1 WO 2025064750A1
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WIPO (PCT)
Prior art keywords
compound
inhibitor
additional therapeutic
therapeutic agent
cancer
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Pending
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PCT/US2024/047598
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English (en)
Inventor
Claire L. NEILAN
Diana Marcela MUNOZ DELGADO
Michael Anthony White
Reeja MASKEY
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Ideaya Biosciences Inc
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Ideaya Biosciences Inc
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Publication of WO2025064750A1 publication Critical patent/WO2025064750A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • SSBs Single-strand breaks
  • PARG Poly ADP-ribose glycohydrolase
  • PARP poly ADP-ribose polymerase
  • PARP poly ADP-ribose polymerase
  • PARG poly ADP-ribose polymerase
  • ARH3 Another known protein with glycohydrolase activity is ARH3 which is localized to the mitochondria.
  • PARG impacts PAR signaling in splicing, transcriptional and epigenetic pathways. Cancer cels may become reliant upon a specific DNA repair pathway when other mechanisms of DNA repair are non-functional. Tumors carying mutations in proteins involved in double strand break repair are often more sensitive to PARP inhibitors of SSBR. There is already some evidence that PARG depletion inhibits SSBR and reduces survival of BRCA2-deficient cels. However, other tumor mutations may give rise to deficiencies in double strand DNA repair mechanisms (so-caled “BRCA-ness”) thereby sensitizing tumor cels to PARG inhibition.
  • SUMMARY Provided herein is a combination comprising a Poly ADP-ribose glycohydrolase (PARG) inhibitor and an additional therapeutic agent.
  • PARG Poly ADP-ribose glycohydrolase
  • the combination is useful for the treatment of a variety of cancers, including solid tumors.
  • the disease or disorder is an advanced or metastatic solid tumor.
  • the combination is also useful for the treatment of any number of PARG-associated diseases.
  • the combination is also useful for the treatment of a variety of diseases or disorders in which PARG activity is implicated.
  • the combination is useful for treating a homologous recombinant deficient (HRD) cancer.
  • a combination product comprising a PARG inhibitor and an additional therapeutic agent.
  • the combination product is useful for the treatment of a variety of cancers, including solid tumors.
  • the disease or disorder is an advanced or metastatic solid tumor.
  • the combination product is also useful for the treatment of any number of PARG-associated diseases.
  • the combination product is also useful for the treatment of a variety of diseases or disorders in which PARG activity is implicated.
  • the combination product is useful for the treatment of a homologous recombinant deficient (HRD) cancer.
  • provided herein is a combination of a PARG inhibitor and an additional therapeutic agent.
  • a pharmaceutical composition comprising a therapeuticaly effete amount of a PARG inhibitor and a second pharmaceutical composition comprising a therapeuticaly effete amount of an additional therapeutic agent.
  • methods of treating and/or preventing cancer in a subject in need thereof comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent, thereby treating the cancer in the subject.
  • provided herein are methods of treating and or preventing cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent together with at least a pharmaceuticaly acceptable carrier, thereby treating the cancer in the subject.
  • Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT In an embodiment are methods of treating and/or preventing a homologous recombinant deficient (HRD) cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent, thereby treating the cancer in the subject.
  • HRD homologous recombinant deficient
  • the methods comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent together with at least a pharmaceuticaly acceptable carier, thereby treating the cancer in the subject.
  • the cancer is characterized by a reduction or absence of BRCA1 and/or BRCA2 gene expression, the absence or mutation of BRCA1 and/or BRCA2 genes, or reduced function of BRCA1 and/or BRCA2 proteins, or combination thereof.
  • provided herein are methods of treating and/or preventing cancer in a subject in need thereof, the methods comprising administering to the subject a therapeuticaly effete amount of a pharmaceutical composition comprising a PARG inhibitor and a therapeuticaly effete amount of a pharmaceutical composition comprising an additional therapeutic agent, thereby treating the cancer in the subject.
  • methods of treating and/or preventing a disease or disorder in which PARG activity is implicated in a subject in need thereof the methods comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent, thereby treating the disease or disorder in the subject.
  • the disease or disorder is cancer.
  • provided herein are methods of treating and/or preventing a disease or disorder in which PARG activity is implicated in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent, together with at least a pharmaceuticaly acceptable carrier, thereby treating the disease or disorder in the subject.
  • the cancer is a homologous recombination deficient (HRD) cancer.
  • the PARG inhibitor is a compound of Formula I: Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT or a pharmaceuticaly acceptable salt thereof, wherein the variables of Formula I are defined below.
  • the PARG inhibitor is 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2- yl)-4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6- sulfonamide (Compound 1) having the folowing structural formula: or a pharmaceuticaly acceptable salt thereof. Methods of making Compound 1 are provided in Example 1 of this application.
  • PARG inhibitors as described in WO2021/055744 (PCT/US20/51486) can be used to treat cancer as described herein. The entire contents of WO2021/055744 is hereby incorporated by reference in its entirety.
  • the additional therapeutic agent is an agent described herein. In an embodiment, the additional therapeutic agent is gemcitabine. In an embodiment, the additional therapeutic agent is paclitaxel. In an embodiment, the additional therapeutic agent is Ku60019. In an embodiment, the additional therapeutic agent is AZD0156. In an embodiment, the additional therapeutic agent is ceralasertib. In an embodiment, the additional therapeutic agent is camonsertib. In an embodiment, the additional therapeutic agent is VE821. In an embodiment, the additional therapeutic agent is AZD6672. In an embodiment, the additional therapeutic agent is SRA737. In an embodiment, the additional therapeutic agent is rabusertib. In an embodiment, the additional therapeutic agent is prexasertib.
  • the additional therapeutic agent is SCH900776. In an embodiment, the additional therapeutic agent is adavosertib. In an embodiment, the additional therapeutic agent is cladribine. In an embodiment, the additional therapeutic agent is clofarabine. In an embodiment, the additional therapeutic agent is cytarabine. In an embodiment, the additional therapeutic agent is floxuridine. In an embodiment, the additional therapeutic agent is raloxifene. In an embodiment, the additional therapeutic agent is mechlorethamine. In an embodiment, the additional therapeutic agent is perfosamide. In an embodiment, the additional therapeutic agent is carboplatin. In an embodiment, the Mintz Docket No.052326-573001WO IDY Ref.
  • No.2023-029-D-PCT additional therapeutic agent is cisplatin.
  • the additional therapeutic agent is satraplatin.
  • the additional therapeutic agent is nivolumab.
  • the additional therapeutic agent is pembrolizumab.
  • the additional therapeutic agent is cemiplimab.
  • the additional therapeutic agent is dostarlimab.
  • the additional therapeutic agent is zimberelimab.
  • the additional therapeutic agent is retifanlimab.
  • the additional therapeutic agent is atezolizumab.
  • the additional therapeutic agent is avelumab.
  • the additional therapeutic agent is atezolizumab.
  • the additional therapeutic agent is durvalumab.
  • FIGs.1A and 1B show eficacy study assessing combination effectss between Compound 1 and Gemcitabine in the HR deficient breast cancer line HCC1428 (ER+/PR+/HER2- BRCA2mut).
  • FIG.1A plots meant tumor mass as a function of days;
  • FIG. 1B the same plot as FIG.1A where the y axis is limited to a mean tumor volume of 800 mm3.
  • FIGs.2A and 2B show eficacy study assessing combination effectss between Compound 1 and carboplatin in the HR deficient breast cancer line HCC1428 (ER+/PR+/HER2- BRCA2mut).
  • FIG.2A plots meant tumor mass as a function of days; FIG. 2B the same plot as FIG.2A where the y axis is limited to a mean tumor volume of 800 mm3.
  • FIGs.3A and 3B show eficacy study assessing combination effectss between Compound 1 and paclitaxel in the HR deficient breast cancer line HCC1428 (ER+/PR+/HER2- BRCA2mut).
  • FIG.3A plots meant tumor mass as a function of days; FIG. 3B the same plot as FIG.3A where the y axis is limited to a mean tumor volume of 800 mm3.
  • FIG.4 shows eficacy study assessing combination effectss between Compound 1 and the anti-mouse PD-1 inhibitor RMP1-14 in the syngeneic mouse line H22.
  • the displayed graph plots mean tumor mass as a function of days.
  • FIGs.5A to 5N show growth inhibition of Compound 1 and Carboplatin in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.5A); BT-549 (FIG.5B); CAL-51 (FIG.5C); Caov-3 (FIG.5D); HCC38 (FIG. Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT 5E); HCC1937 (FIG.5F); HCC1954 (FIG.5G); KPL-1 (FIG.5H); MCF7 (FIG.5I); OVCAR-8 (FIG.5J); OVSAHO (FIG.5K); PA-1 (FIG.5L); SK-OV-3 (FIG.5M); T47D (FIG.5N).
  • FIGs.6A to 6N show Loewe Synergy of Compound 1 and Carboplatin in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Carboplatin using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.6A); BT-549 (FIG.6B); CAL-51 (FIG.6C); Caov-3 (FIG.6D); HCC38 (FIG.6E); HCC1937 (FIG.6F); HCC1954 (FIG.6G); KPL-1 (FIG.6H); MCF7 (FIG.6I); OVCAR-8 (FIG.6J); OVSAHO (FIG.6K); PA-1 (FIG.6L); SK-OV-3 (FIG.6M); T47D (FIG. 6N).
  • FIGs.7A to 7N show growth inhibition of Compound 1 and Cisplatin in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.7A); BT-549 (FIG.7B); CAL-51 (FIG.7C); Caov-3 (FIG.7D); HCC38 (FIG.
  • FIGs.8A to 8N show Loewe Synergy of Compound 1 and Cisplatin in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Cisplatin using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • FIGs.9A to 9N show growth inhibition of Compound 1 and Satraplatin in 14 breast and ovarian cel lines.
  • FIGs.10A to 10N show Loewe Synergy of Compound 1 and Satraplatin in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Mintz Docket No.052326-573001WO IDY Ref.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.10A); BT-549 (FIG.10B); CAL-51 (FIG.10C); Caov-3 (FIG.10D); HCC38 (FIG.10E); HCC1937 (FIG.10F); HCC1954 (FIG.10G); KPL-1 (FIG.10H); MCF7 (FIG.10I); OVCAR-8 (FIG.10J); OVSAHO (FIG.10K); PA-1 (FIG.10L); SK-OV-3 (FIG.
  • FIGs.11A to 11N show growth inhibition of Compound 1 and Compound 2 in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.11A); BT-549 (FIG.11B); CAL-51 (FIG.11C); Caov-3 (FIG.11D); HCC38 (FIG.11E); HCC1937 (FIG.11F); HCC1954 (FIG.11G); KPL-1 (FIG.11H); MCF7 (FIG.11I); OVCAR-8 (FIG.11J); OVSAHO (FIG.11K); PA-1 (FIG.11L); SK-OV-3 (FIG. 11M); T47D (FIG.11N).
  • FIGs.12A to 12N show Loewe Synergy of Compound 1 and Compound 2 in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Compound 2 using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • FIGs.13A to 13N show growth inhibition of Compound 1 and Compound 3 in 14 breast and ovarian cel lines.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.13A); BT-549 (FIG.13B); CAL-51 (FIG.13C); Caov-3 (FIG.13D); HCC38 (FIG.13E); HCC1937 (FIG.13F); HCC1954 (FIG.13G); KPL-1 (FIG.13H); MCF7 (FIG.13I); OVCAR-8 (FIG.13J); OVSAHO (FIG.13K); PA-1 (FIG.13L); SK-OV-3 (FIG.
  • FIGs.14A to 14N show Loewe Synergy of Compound 1 and Compound 3 in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Compound 3 using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic. Panels A to N display the Mintz Docket No.052326-573001WO IDY Ref.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.15A); BT-549 (FIG.15B); CAL-51 (FIG.15C); Caov-3 (FIG.15D); HCC38 (FIG.15E); HCC1937 (FIG.15F); HCC1954 (FIG.15G); KPL-1 (FIG.15H); MCF7 (FIG.15I); OVCAR-8 (FIG.15J); OVSAHO (FIG.15K); PA-1 (FIG.15L); SK-OV-3 (FIG. 15M); T47D (FIG.15N).
  • FIGs.16A to 16N show Loewe Synergy of Compound 1 and Ceralasertib in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Ceralasertib using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.16A); BT-549 (FIG.16B); CAL-51 (FIG.16C); Caov-3 (FIG.16D); HCC38 (FIG.16E); HCC1937 (FIG.16F); HCC1954 (FIG.16G); KPL-1 (FIG.16H); MCF7 (FIG.16I); OVCAR-8 (FIG.16J); OVSAHO (FIG.16K); PA-1 (FIG.16L); SK-OV-3 (FIG.16M); T47D (FIG.16N).
  • FIGs.17A to 17N show growth inhibition of Compound 1 and Camonsertib in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.17A); BT-549 (FIG.17B); CAL-51 (FIG.17C); Caov-3 (FIG.17D); HCC38 (FIG.17E); HCC1937 (FIG.17F); HCC1954 (FIG.17G); KPL-1 (FIG.17H); MCF7 (FIG.17I); OVCAR-8 (FIG.17J); OVSAHO (FIG.17K); PA-1 (FIG.17L); SK-OV-3 (FIG. 17M); T47D (FIG.17N).
  • FIGs.18A to 18N show Loewe Synergy of Compound 1 and Camonsertib in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Camonsertib using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.18A); BT-549 (FIG.18B); CAL-51 (FIG.18C); Caov-3 (FIG.18D); HCC38 (FIG.18E); HCC1937 (FIG.18F); HCC1954 (FIG.18G); KPL-1 Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT (FIG.18H); MCF7 (FIG.18I); OVCAR-8 (FIG.18J); OVSAHO (FIG.18K); PA-1 (FIG.18L); SK-OV-3 (FIG.18M); T47D (FIG.18N).
  • FIGs.19A to 19N show growth inhibition of Compound 1 and Compound 4 in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.19A); BT-549 (FIG.19B); CAL-51 (FIG.19C); Caov-3 (FIG.19D); HCC38 (FIG.19E); HCC1937 (FIG.19F); HCC1954 (FIG.19G); KPL-1 (FIG.19H); MCF7 (FIG.19I); OVCAR-8 (FIG.19J); OVSAHO (FIG.19K); PA-1 (FIG.19L); SK-OV-3 (FIG. 19M); T47D (FIG.19N).
  • FIGs.20A to 20N show Loewe Synergy of Compound 1 and Compound 4 in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Compound 4 using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • FIGs.21A to 21N show growth inhibition of Compound 1 and Compound 5 in 14 breast and ovarian cel lines.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.21A); BT-549 (FIG.21B); CAL-51 (FIG.21C); Caov-3 (FIG.21D); HCC38 (FIG.21E); HCC1937 (FIG.21F); HCC1954 (FIG.21G); KPL-1 (FIG.21H); MCF7 (FIG.21I); OVCAR-8 (FIG.21J); OVSAHO (FIG.21K); PA-1 (FIG.21L); SK-OV-3 (FIG.
  • FIGs.22A to 22N show Loewe Synergy of Compound 1 and Compound 5 in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Compound 5 using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.22A); BT-549 (FIG.22B); CAL-51 (FIG.22C); Caov-3 (FIG.22D); HCC38 (FIG.22E); HCC1937 (FIG.22F); HCC1954 (FIG.22G); KPL-1 (FIG.22H); MCF7 (FIG.22I); OVCAR-8 (FIG.22J); OVSAHO (FIG.22K); PA-1 (FIG.22L); SK-OV-3 (FIG.22M); T47D (FIG.22N). Mintz Docket No.052326-573001WO IDY Ref.
  • FIGs.23A to 23N show growth inhibition of Compound 1 and Compound 6 in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.23A); BT-549 (FIG.23B); CAL-51 (FIG.23C); Caov-3 (FIG.23D); HCC38 (FIG.23E); HCC1937 (FIG.23F); HCC1954 (FIG.23G); KPL-1 (FIG.23H); MCF7 (FIG.23I); OVCAR-8 (FIG.23J); OVSAHO (FIG.23K); PA-1 (FIG.23L); SK-OV-3 (FIG. 23M); T47D (FIG.23N).
  • FIGs.24A to 24N show Loewe Synergy of Compound 1 and Compound 6 in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Compound 6 using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.24A); BT-549 (FIG.24B); CAL-51 (FIG.24C); Caov-3 (FIG.24D); HCC38 (FIG.24E); HCC1937 (FIG.24F); HCC1954 (FIG.24G); KPL-1 (FIG.24H); MCF7 (FIG.24I); OVCAR-8 (FIG.24J); OVSAHO (FIG.24K); PA-1 (FIG.24L); SK-OV-3 (FIG.24M); T47D (FIG.24N).
  • FIGs.25A to 25N show growth inhibition of Compound 1 and Rabusertib in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.25A); BT-549 (FIG.25B); CAL-51 (FIG.25C); Caov-3 (FIG.25D); HCC38 (FIG.25E); HCC1937 (FIG.25F); HCC1954 (FIG.25G); KPL-1 (FIG.25H); MCF7 (FIG.25I); OVCAR-8 (FIG.25J); OVSAHO (FIG.25K); PA-1 (FIG.25L); SK-OV-3 (FIG.25M); T47D (FIG.25N).
  • FIGs.26A to 26N show Loewe Synergy of Compound 1 and Rabusertib in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Rabusertib using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.26A); BT-549 (FIG.26B); CAL-51 (FIG.26C); Caov-3 (FIG.26D); HCC38 (FIG.26E); HCC1937 (FIG.26F); HCC1954 (FIG.26G); KPL-1 (FIG.26H); MCF7 (FIG.26I); OVCAR-8 (FIG.26J); OVSAHO (FIG.26K); PA-1 (FIG.26L); SK-OV-3 (FIG. 26M); T47D (FIG.26N).
  • FIGs.27A to 27N show growth inhibition of Compound 1 and Prexasertib in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.27A); BT-549 (FIG.27B); CAL-51 (FIG.27C); Caov-3 (FIG.27D); HCC38 (FIG.27E); HCC1937 (FIG.27F); HCC1954 (FIG.27G); KPL-1 (FIG.27H); MCF7 (FIG.27I); OVCAR-8 (FIG.27J); OVSAHO (FIG.27K); PA-1 (FIG.27L); SK-OV-3 (FIG. 27M); T47D (FIG.27N).
  • FIGs.28A to 28N show Loewe Synergy of Compound 1 and Prexasertib in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Prexasertib using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • FIGs.29A to 29N show growth inhibition of Compound 1 and Compound 7 in 14 breast and ovarian cel lines.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.29A); BT-549 (FIG.29B); CAL-51 (FIG.29C); Caov-3 (FIG.29D); HCC38 (FIG.29E); HCC1937 (FIG.29F); HCC1954 (FIG.29G); KPL-1 (FIG.29H); MCF7 (FIG.29I); OVCAR-8 (FIG.29J); OVSAHO (FIG.29K); PA-1 (FIG.29L); SK-OV-3 (FIG.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.30A); BT-549 (FIG.30B); CAL-51 (FIG.30C); Caov-3 (FIG.30D); HCC38 (FIG.30E); HCC1937 (FIG.30F); HCC1954 (FIG.30G); KPL-1 (FIG.30H); MCF7 (FIG.30I); OVCAR-8 (FIG.30J); OVSAHO (FIG.30K); PA-1 (FIG.30L); SK-OV-3 (FIG.30M); T47D (FIG.30N).
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.31A); BT-549 (FIG.31B); CAL-51 (FIG.31C); Caov-3 (FIG.31D); HCC38 (FIG.31E); HCC1937 (FIG.31F); HCC1954 (FIG.31G); KPL-1 (FIG.31H); MCF7 (FIG.31I); OVCAR-8 (FIG.31J); OVSAHO (FIG.31K); PA-1 (FIG.31L); SK-OV-3 (FIG. 31M); T47D (FIG.31N).
  • FIGs.32A to 32N show Loewe Synergy of Compound 1 and Adavosertib in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Adavosertib using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.32A); BT-549 (FIG.32B); CAL-51 (FIG.32C); Caov-3 (FIG.32D); HCC38 (FIG.32E); HCC1937 (FIG.32F); HCC1954 (FIG.32G); KPL-1 (FIG.32H); MCF7 (FIG.32I); OVCAR-8 (FIG.32J); OVSAHO (FIG.32K); PA-1 (FIG.32L); SK-OV-3 (FIG. 32M); T47D (FIG.32N).
  • FIGs.33A to 33N show growth inhibition of Compound 1 and Cladribine in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.33A); BT-549 (FIG.33B); CAL-51 (FIG.33C); Caov-3 (FIG.33D); HCC38 (FIG.33E); HCC1937 (FIG.33F); HCC1954 (FIG.33G); KPL-1 (FIG.33H); MCF7 (FIG.33I); OVCAR-8 (FIG.33J); OVSAHO (FIG.33K); PA-1 (FIG.33L); SK-OV-3 (FIG.33M); T47D (FIG.33N).
  • FIGs.34A to 34N show Loewe Synergy of Compound 1 and Cladribine in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Cladribine using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.34A); BT-549 (FIG.34B); CAL-51 (FIG.34C); Caov-3 (FIG.34D); HCC38 (FIG.34E); HCC1937 (FIG.34F); HCC1954 (FIG.34G); KPL-1 (FIG.34H); MCF7 (FIG.34I); OVCAR-8 (FIG.34J); OVSAHO (FIG.34K); PA-1 (FIG.34L); SK-OV-3 (FIG. 34M); T47D (FIG.34N).
  • FIGs.35A to 35N show growth inhibition of Compound 1 and Clofarabinblisse in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.35A); BT-549 (FIG.35B); CAL-51 (FIG.35C); Caov-3 (FIG.35D); Mintz Docket No.052326-573001WO IDY Ref.
  • FIGs.36A to 36N show Loewe Synergy of Compound 1 and Clofarabine in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Clofarabine using the Loewe additivity model for each cel line.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.36A); BT-549 (FIG.36B); CAL-51 (FIG.36C); Caov-3 (FIG.36D); HCC38 (FIG.36E); HCC1937 (FIG.36F); HCC1954 (FIG.36G); KPL-1 (FIG.36H); MCF7 (FIG.36I); OVCAR-8 (FIG.36J); OVSAHO (FIG.36K); PA-1 (FIG.36L); SK-OV-3 (FIG. 36M); T47D (FIG.36N).
  • FIGs.37A to 37N show growth inhibition of Compound 1 and Cytarabine in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.37A); BT-549 (FIG.37B); CAL-51 (FIG.37C); Caov-3 (FIG.37D); HCC38 (FIG.37E); HCC1937 (FIG.37F); HCC1954 (FIG.37G); KPL-1 (FIG.37H); MCF7 (FIG.37I); OVCAR-8 (FIG.37J); OVSAHO (FIG.37K); PA-1 (FIG.37L); SK-OV-3 (FIG.37M); T47D (FIG.37N).
  • FIGs.38A to 38N show Loewe Synergy of Compound 1 and Cytarabine in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Cytarabine using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.38A); BT-549 (FIG.38B); CAL-51 (FIG.38C); Caov-3 (FIG.38D); HCC38 (FIG.38E); HCC1937 (FIG.38F); HCC1954 (FIG.38G); KPL-1 (FIG.38H); MCF7 (FIG.38I); OVCAR-8 (FIG.38J); OVSAHO (FIG.38K); PA-1 (FIG.38L); SK-OV-3 (FIG. 38M); T47D (FIG.38N).
  • FIGs.39A to 39N show growth inhibition of Compound 1 and Gemcitabine Hydrochloride in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.39A); BT-549 (FIG.39B); CAL-51 (FIG.39C); Caov-3 (FIG.39D); HCC38 (FIG.39E); HCC1937 (FIG.39F); HCC1954 (FIG.39G); KPL-1 Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT (FIG.39H); MCF7 (FIG.39I); OVCAR-8 (FIG.39J); OVSAHO (FIG.39K); PA-1 (FIG.39L); SK-OV-3 (FIG.39M); T47D (FIG.39N).
  • FIGs.40A to 40N show Loewe Synergy of Compound 1 and Gemcitabine Hydrochloride in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Gemcitabine Hydrochloride using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic. Panels A to N display the results with diferent cel lines: BT-474 (FIG.40A); BT- 549 (FIG.40B); CAL-51 (FIG.40C); Caov-3 (FIG.40D); HCC38 (FIG.40E); HCC1937 (FIG.
  • FIGs.41A to 41N show Growth inhibition of Compound 1 and Floxuridine in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.41A); BT-549 (FIG.41B); CAL-51 (FIG.41C); Caov-3 (FIG.41D); HCC38 (FIG.41E); HCC1937 (FIG.41F); HCC1954 (FIG.41G); KPL-1 (FIG.41H); MCF7 (FIG.41I); OVCAR-8 (FIG.41J); OVSAHO (FIG.41K); PA-1 (FIG.41L); SK-OV-3 (FIG. 41M); T47D (FIG.41N).
  • FIGs.42A to 42N show Loewe Synergy of Compound 1 and Floxuridine in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Floxuridine using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.42A); BT-549 (FIG.42B); CAL-51 (FIG.42C); Caov-3 (FIG.42D); HCC38 (FIG.42E); HCC1937 (FIG.42F); HCC1954 (FIG.42G); KPL-1 (FIG.42H); MCF7 (FIG.42I); OVCAR-8 (FIG.42J); OVSAHO (FIG.42K); PA-1 (FIG.42L); SK-OV-3 (FIG. 42M); T47D (FIG.42N).
  • FIGs.43A to 43N show growth inhibition of Compound 1 and Mechlorethamine Hydrochloride in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.43A); BT-549 (FIG.43B); CAL-51 (FIG.43C); Caov-3 (FIG.43D); HCC38 (FIG.43E); HCC1937 (FIG.43F); HCC1954 (FIG.43G); KPL-1 (FIG.43H); MCF7 (FIG.43I); OVCAR-8 (FIG.43J); OVSAHO (FIG.43K); PA-1 (FIG.43L); SK-OV-3 (FIG.43M); T47D (FIG.43N). Mintz Docket No.052326-573001WO IDY Ref.
  • FIGs.44A to 44N show Loewe Synergy of Compound 1 and Mechlorethamine Hydrochloride in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Mechlorethamine Hydrochloride using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.44A); BT-549 (FIG.44B); CAL-51 (FIG.44C); Caov-3 (FIG.44D); HCC38 (FIG.44E); HCC1937 (FIG.44F); HCC1954 (FIG.44G); KPL-1 (FIG.44H); MCF7 (FIG.44I); OVCAR-8 (FIG.44J); OVSAHO (FIG.44K); PA-1 (FIG.44L); SK-OV-3 (FIG.44M); T47D (FIG.44N).
  • FIGs.45A to 45N show growth inhibition of Compound 1 and Perfosamide in 14 breast and ovarian cel lines. Growth inhibition is presented as a percent of T0 for each cel line in a 6x6 dose matrix.50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.45A); BT-549 (FIG.45B); CAL-51 (FIG.45C); Caov-3 (FIG.45D); HCC38 (FIG.45E); HCC1937 (FIG.45F); HCC1954 (FIG.45G); KPL-1 (FIG.45H); MCF7 (FIG.45I); OVCAR-8 (FIG.45J); OVSAHO (FIG.45K); PA-1 (FIG.45L); SK-OV-3 (FIG. 45M); T47D (FIG.45N).
  • FIGs.46A to 46N show Loewe Synergy of Compound 1 and Perfosamide in 14 breast and ovarian cel lines. Synergy is measured at al tested concentrations of Compound 1 and Perfosamide using the Loewe additivity model for each cel line. Scores >20 are highlighted in dark gray and are considered synergistic.
  • Panels A to N display the results with diferent cel lines: BT-474 (FIG.46A); BT-549 (FIG.46B); CAL-51 (FIG.46C); Caov-3 (FIG.46D); HCC38 (FIG.46E); HCC1937 (FIG.46F); HCC1954 (FIG.46G); KPL-1 (FIG.46H); MCF7 (FIG.46I); OVCAR-8 (FIG.46J); OVSAHO (FIG.46K); PA-1 (FIG.46L); SK-OV-3 (FIG.46M); T47D (FIG.46N).
  • FIG.47 shows eficacy study assessing combination effectss between Compound 1 and Compound 8 in the non-smal cel lung cancer model NCI-H647.
  • FIG.48 shows Loewe Synergy of Compound 1 and Compound 8 in MTAP-nul gastric cancer cel line.
  • DETAILED DESCRIPTION Provided herein is a combination therapy comprising a PARG inhibitor, or a pharmaceuticaly acceptable salt thereof, and an additional therapeutic agent, or a pharmaceuticaly acceptable salt thereof.
  • the combination therapy is useful for the treatment of a variety of cancers, including, for example, ovarian, gastric, breast, lung, cervical, pancreatic, or prostate cancer.
  • the combination therapy is useful for the Mintz Docket No.052326-573001WO IDY Ref.
  • No.2023-029-D-PCT treatment of any number of PARG-associated diseases is useful for the treatment of any number of PARG-mediated diseases.
  • the combination therapy is useful for the treatment of any disease or disorder treatable by inhibiting PARG.
  • Administering a combination of a PARG inhibitor and an additional therapeutic agent can provide beneficial effectss for treating cancer, e.g., solid tumors, in a subject.
  • Such an approach – combination or co-administration of the two types of agents, i.e., a PARG inhibitor and an additional therapeutic agent – may ofer an uninterupted treatment to a subject in need over a clinicaly relevant treatment period. Definitions Listed below are definitions of various terms used herein.
  • the term “comprising” may include the embodiments “consisting of” and “consisting essentialy of.”
  • the terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients/steps and permit the presence of other ingredients/steps. It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is to be understood that such a range format Mintz Docket No.052326-573001WO IDY Ref.
  • No.2023-029-D-PCT is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include al the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.
  • the phrase “about ‘x’ to ‘y’” includes “about ‘x’ to about ‘y’”.
  • combination refers to either a fixed combination in one dosage unit form, or non-fixed combination in separate dosage forms, or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently, at the same time or separately within time intervals.
  • combination therapy refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantialy simultaneous manner, such as in a single formulation having a fixed ratio of active ingredients or in separate formulations (e.g., capsules and/or intravenous formulations) for each active ingredient.
  • such administration also encompasses use of each type of therapeutic agent in a sequential or separate manner, either at approximately the same time or at diferent times.
  • the active ingredients are administered as a single formulation or in separate formulations, the drugs are administered to the same patient as part of the same course of therapy.
  • the treatment regimen wil provide beneficial effectss in treating the conditions or disorders described herein.
  • treating refers to inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., arresting further development of the pathology and/or symptomology) or ameliorating the disease; for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and/or symptomology) such as decreasing the severity of the disease.
  • the term “patient,” “individual,” or “subject” refers to a human.
  • the terms “efective amount,” “pharmaceuticaly effete amount,” and “therapeuticaly effete amount” refer to a nontoxic but adequate amount of an agent to provide the desired biological result. That result may be reduction or aleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • An Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT appropriate therapeutic amount in any individual case may be determined by one of ordinary skil in the art using routine experimentation.
  • the term “pharmaceuticaly acceptable” refers to a material, such as a carier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceuticalaly acceptable salt refers to derivatives of the disclosed compounds wherein a parent compound is modified by converting an existing acid or base moiety to its salt form.
  • Examples of pharmaceuticaly acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceuticaly acceptable salts described herein include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceuticaly acceptable salts discussed herein can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generaly, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • pharmaceuticalaly acceptable salt is not limited to a mono, or 1:1, salt.
  • “pharmaceuticaly acceptable salt” also includes bis-salts, such as a bis-hydrochloride salt.
  • compositions or “pharmaceutical composition” refers to a mixture of at least one compound with a pharmaceuticaly acceptable carrier.
  • the pharmaceutical composition facilitates administration of the composition to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
  • the term “pharmaceuticaly acceptable carier” means a pharmaceuticaly acceptable material, composition or carrier, such as a liquid or solid filer, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carying or transporting a compound useful to the patient such that it may perform its intended function. Typicaly, such constructs are caried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound disclosed herein, and not injurious to the patient.
  • materials that may serve as pharmaceuticaly acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; celulose, and its derivatives, such as sodium carboxymethyl celulose, ethyl celulose and celulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa buter and suppository waxes; oils, such as peanut oil, Laceed oil, saflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as Mintz Docket No.052326-573001WO IDY Ref.
  • sugars such as lactose, glucose and sucrose
  • starches such as corn starch and potato starch
  • celulose, and its derivatives such as sodium carboxymethyl
  • No.2023-029-D-PCT ethyl oleate and ethyl laurate; agar; bufering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate bufer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.
  • pharmaceuticalaly acceptable carier also includes any and al coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of a compound disclosed herein, and are physiologicaly acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • single formulation refers to a single carrier or vehicle formulated to deliver therapeuticaly effete amounts of both therapeutic agents to a patient.
  • the single vehicle is designed to deliver a therapeuticaly effete amount of each of the agents, along with any pharmaceuticaly acceptable carriers or excipients.
  • the vehicle is a tablet, capsule, pil, or a patch. In other embodiments, the vehicle is a solution or a suspension.
  • Poly ADP-ribose glycohydrolase inhibitor or “PARG inhibitor” means an agent that modulates the activity of PARG.
  • a combination therapy comprising a therapeuticaly effete amount of a PARG inhibitor and an additional therapeutic agent.
  • a “therapeuticaly effete amount” of a combination of agents i.e., a PARG inhibitor and an additional therapeutic agent
  • Observable improvements include those that can be visualy ascertained by a clinician and biological tests, biopsies, and assays.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e. C1-8 means one to eight carbons).
  • Alkyl can include any number of carbons, such as C1-2, C1-3, C1-4, C1-5, C1-6, C1-7, C1-8, C1-9, C1-10, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6.
  • alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT The term “Ameliorate” or “amelioration” includes the arrest, prevention, decrease, or improvement in one or more the symptoms, signs, and features of the disease being treated, both temporary and long-term.
  • cycloalkyl refers to a saturated hydrocarbon ring having the indicated number of ring atoms (e.g., C3-6 cycloalkyl). Cycloalkyl is optionaly substituted with one, two, or three substituents independently selected from C1-6 alkyl, halo, hydroxy, C1-6 haloalkyl, C1-6haloalkoxy, or cyano, unless stated otherwise. Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • halo or "halogen,” by itself or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • haloalkyl means alkyl, as defined above, that is substituted with one to five halo atoms and includes monohaloalkyl and polyhaloalkyl.
  • C1-4 haloalkyl includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • alkoxy and haloalkoxy refer to alkyl and haloalkyl groups respectively, each as defined herein, that is atached to the remainder of the molecule via an oxygen atom.
  • heteroaryl refers to a 5- to 10-membered aromatic ring that contains from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionaly oxidized, and the nitrogen atom(s) are optionaly quaternized.
  • a heteroaryl group can be atached to the remainder of the molecule through a heteroatom.
  • heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, p
  • heterocycloalkyl or “heterocyclyl” refers to a saturated or partialy unsaturated 4 to 10 membered monocyclic or bicyclic ring having from one to four heteroatoms independently selected from N, O, and S and the remaining ring atom being carbon.
  • heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S- Mintz Docket No.052326-573001WO IDY Ref.
  • a heterocycloalkyl group can be atached to the remainder of the molecule through a ring carbon or a heteroatom.
  • heterocycloalkyl groups include pyridine-2(H)-one.
  • hydroxyalkyl means alkyl, as defined above, that is substituted with one or two hydroxy.
  • hydroxyC1-4alkyl is mean to include hydroxymethyl, 1-, or 2-hydroxyethyl, 1,2-dihydroxyethyl, hydroxypropyl, and the like.
  • homologous recombination refers to the celular process of genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNA sequences.
  • homologous recombination deficient (HRD) cancer refers to a cancer that is characterized by a reduction or absence of a functional HR repair pathway. HR deficiency may arise from absence or reduction of one or more HR-associated genes or presence of one or more mutations in one or more HR-associated genes.
  • HR-associated genes include BRCA1, BRCA2, RAD54, RAD51B, ATM, BARD1, CHK1, CHK2, CDK12, RAD51B, RAD54L, RAD51D, PPP22A, BRIP1, CtIP (CtBP-interacting protein), PALB2 (Partner and Localizer of BRCA2), XRCC2 (X-ray repair complementing defective repair in Chinese hamster cels 2), RECQL4 (RecQ Protein-Like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome , one or more HR- associated genes) Nbs 1 (Nibrin), and genes encoding Fanconi anemia (FA) proteins or FA- like genes e.g, FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANC
  • MSI microsatelite instability
  • MSI-H microsatelite instability-high
  • MSI-L microsatelite instability-low
  • MSS microsatelite stable.
  • Microsatelites are repetitive DNA sequences with varying unit lengths (e.g. ranging from one base (mononucleotide) to six bases (di-, tri-, tetra-, penta-, esa-nucleotides)) distributed along coding and/or noncoding regions of the genome. Mutations of such microsatelites, for example, repeat length alterations, can represent microsatelite instability.
  • MSI can be detected (e.g., directly) by molecular testing (e.g., with respect to certain microsatelites) or (e.g., indirectly) by immunohistochemical evaluation (e.g., with respect to expression of certain MMR proteins). Based on a consensus NCI-Reference Panel (Bethesda, 1998), MSI can be assessed by molecular testing of five microsatelites – including two mononucleotides (BAT25 and BAT26) and three dinucleotides (D2S123, D5S346, D17S250).
  • Tumors can be classified into diferent subtypes based on such a NCI-Reference Panel approach for Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT molecular testing, including microsatelite instability-high (MSI-H) if two or more of the microsatelite markers show instability, MSI-low (MSI-L) if only one microsatelite marker shows instability, and microsatelite stable (MSS) if none of the five microsatelite markers show instability (i.e., each of the five microsatelite markers are determined as stable).
  • MSI-H microsatelite instability-high
  • MSI-L MSI-low
  • MSS microsatelite stable
  • the antibodies disclosed in the antibody drug conjugate of the present disclosure means an immunoglobulin and is a molecule containing an antigen-binding site immunospecificaly binding to an antigen.
  • the class of the antibody of the present disclosure may be any of IgG, IgE, IgM, IgD, IgA, and IgY and is preferably IgG.
  • the subclass of the antibody of the present disclosure may be any of IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2 and is preferably IgGl or IgG2.
  • the antibody may be derived from any species, and prefered examples of the species can include humans, rats, mice, and rabbits. When the antibody is derived from other than human species, it is preferably chimerized or humanized using a wel-known technique.
  • the antibody of the present disclosure may be a polyclonal antibody or a monoclonal antibody. In an embodiment, the antibody is a monoclonal antibody.
  • the antibody of the present disclosure is capable of targeting tumor cels.
  • the antibody of the present disclosure is conjugated with an antitumor compound having antitumor activity via a linker, the antibody preferably possesses one or more of a property of recognizing a tumor cel, a property of binding to a tumor cel, a property of internalizing in a tumor cel, and a property of damaging a tumor cel.
  • the antibody is a monoclonal antibody that is reactive with a target antigen or epitope of an antigen expressed on a cancer or malignant cel. Techniques for preparing monoclonal antibodies against target antigen are known in the art.
  • Non limiting target antigens are B7-H3, B7-H4, Trop-2, PSMA, folate receptor, EGF receptor (ErbB1), ErbB2, ErbB3, HER-2, tissue factor (TF), CD19, CD22, CD30, CD33, CD79b, CD74, CD138, CD56, CD70, Claudin-18, folate receptor alpha (FR ⁇ ), c-Met, Nectin-4, delta-like ligand 3 (DLL3), PTK7, GPNMB, Ley, CA6, CanAng, Av integrin, SLC44A4, CEACAM5, AGS-16, Anti-Cripto, Carbonic Anhydrase 9, Mesotheilin, TENB2, 5T4, VEGF, insulin-like growth factor (ILGF), MUC1 and TA-MUC1.
  • Combination Product Provided herein is a combination product comprising a PARG inhibitor, or a pharmaceuticaly acceptable salt thereof, and an additional therapeutic agent, or a pharmaceuticaly acceptable salt thereof.
  • the combination product is useful for the treatment of a variety of cancers, including solid tumors.
  • the disease or disorder is Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT an advanced or metastatic solid tumor.
  • the combination product is useful for the treatment of any number of PARG-associated diseases.
  • the combination product is useful for the treatment of a disease or disorder in which PARG activity is implicated.
  • the combination product is useful for the treatment of a homologous recombinant deficient (HRD) cancer.
  • HRD homologous recombinant deficient
  • a combination of a PARG inhibitor and an additional therapeutic agent in an embodiment, provided herein is a combination of a PARG inhibitor and an additional therapeutic agent.
  • the term “combination product” includes embodiments in which the PARG inhibitor and additional therapeutic agent are formulated together into a single pharmaceutical composition (e.g. tablet or capsule), and alternative embodiments in which each therapeutic agent in the combination is individualy formulated into its own pharmaceutical composition and each of the pharmaceutical compositions are administered in the same medical treatment (for example, the same medical treatment of cancer).
  • each of the pharmaceutical compositions may have the same or diferent carriers, diluents or excipients.
  • the combination product comprises first and second pharmaceutical compositions, wherein the first pharmaceutical composition contains Compound 1 (or a pharmaceuticaly acceptable salt thereof), the second pharmaceutical composition contains an additional therapeutic agent, and the first and second pharmaceutical compositions are both administered to treat cancer.
  • the first and second pharmaceutical compositions may be administered simultaneously, separately or sequentialy and in any order. Furthermore, it does not mater if the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered oraly.
  • PARG inhibitors The disclosure provides PARG inhibitors.
  • the PARG inhibitor is a compound of Formula I: Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT (Formula I) or a pharmaceuticaly acceptable salt thereof, wherein: R1 is selected from the group consisting of cyano, C1-2alkyl, and C1-2haloalkyl; Ar is a 5-membered heteroaryl; X2is CH or CF; R2 is selected from the group consisting of C1-3alkyl, C1-3haloalkyl, hydroxyC1-3alkyl, and cyano; ring B is 5- or 6-membered heterocycloalkyl substituted with Ra, Rb, and Rc; Ra is hydrogen, C alkyl, C ha d d 1-4 1-4 loalkyl, halo, hydroxy, or -C(O)R (where R is hydrogen, C1-6alkyl, or C1-6haloalkyl); and Rb and Rc are independently selected from hydrogen, C1-6alkyl
  • the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein R1 is selected from the group consisting of cyano, C1-2alkyl, and C1-2haloalkyl; Ar is a 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X2is CH or CF; R2 is selected from the group consisting of C1-3haloalkyl, C1-3alkyl, hydroxyC1-3alkyl, and cyano; ring B is 5- or 6-membered heterocycloalkyl substituted with Ra, Rb, and Rc; Ra is hydrogen, C alkyl, C haloalkyl, halo, hydroxy, or -C(O)Rd (where d 1-4 1-4 R is hydrogen, C1-6alkyl, or C1-6haloalkyl); and Rb and Rc are independently selected from C1-6alkyl, hydrogen, hydroxy, C1-6alkoxy, halo, C1-6haloalkyl, and C1-6hal
  • the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein X2 is CH. In some embodiments, the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein X2 is CF. In some embodiments, the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein R1 is cyano. In some embodiments, the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein R1 is methyl. In some embodiments, the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein Ar is 1,2,4-thiadiazolyl or 1,3,4-thiadiazol-2-yl.
  • the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein Ar is 1,3,4-thiadiazol-2-yl. Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT In some embodiments, the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein Ar is 1,2,4-thiadiazolyl. In some embodiments, the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein R2 is atached to the carbon atom of Ar that is meta to the atom of Ar that is atached to the nitrogen atom of the remainder of the molecule.
  • the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein R2 is methyl, ethyl, difluoromethyl, trifluoromethyl, or cyano. In some embodiments, the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein R2 is difluoromethyl. In some embodiments, the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein ring B is morpholinyl, 1,1-dioxothiomorpholinyl, pyrrolidinyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl, or piperazinyl.
  • the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein ring B is piperazinyl.
  • the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein Ra is hydrogen, C1-4alkyl, C1-4haloalkyl, halo, hydroxy, or - C(O)Rd (where Rd is hydrogen, C alkyl, or C haloalk b c 1-6 1-6 yl); and R and R are independently selected from hydrogen, C1-6alkyl, hydroxy, C1-6alkoxy, halo, C1-6haloalkyl, and C1-6 haloalkoxy.
  • the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein Ra is hydrogen, C alkyl, o b c 1-4 r C1-4haloalkyl; and R and R are independently selected from hydrogen and C1-6alkyl.
  • the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof wherein Ra is hydrogen, C d 1-4alkyl, C1-4haloalkyl, or -C(O)R (where Rd is C alkyl or C-6ha b c 1-6 1 loalkyl); and R and R are independently selected from hydrogen, C1-6alkyl, and C1-6haloalkoxy.
  • the compound of Formula (I) is Compound 11: Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT Compound 11 or a pharmaceuticaly acceptable salt thereof.
  • the compound of Formula (I) is Compound 11:
  • the compound of Formula (I) is Compound 1: or a pharmaceuticaly acceptable salt thereof.
  • the PARG inhibitor is Compound 1: Mintz Docket No.052326-573001WO IDY Ref.
  • the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is Compound 1.
  • the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is Compound 11.
  • Additional Therapeutic Agents The disclosure provides additional therapeutic agents for use with a PARG inhibitor. A wide variety of therapeutic agents with anti-cancer activity and methods of making the same are known in the art. Each of these is embraced by this disclosure. i) Chemotherapeutic Agents In an embodiment, the additional therapeutic agent is a chemotherapeutic agent. Chemotherapeutic agents include alkylating agent, microtubule inhibitors, antimetabolites, anti-tumor antibiotics, as wel as corticosteroids.
  • the chemotherapeutic agent is an alkylating agent.
  • the alkylating agent is altretamine, bendamustine, busulfan, improsulfan, piposulfan, procarbazine, mechlorethamine, carmustine, lomustine, semustine chlorambucil, cyclophosphamide, thiotepa, ifosfamide, dacarbazine, temozolomide, or perfosamide.
  • the alkylating agent is mechlorethamine.
  • the alkylating agent is perfosamide.
  • the alkylating agent is a platinum-based chemotherapy agent.
  • the alkylating agent is carboplatin, cisplatin, oxaliplatin, nedaplatin, saraplatin, lobaplatin, or heptaplatin. In some embodiments, the alkylating agent is carboplatin. In some embodiments, the alkylating agent is cisplatin. In some embodiments, the alkylating agent is saraplatin. In some embodiments, the chemotherapeutic agent is a microtubule inhibitor.
  • the microtubule inhibitor is eribulin, ixabepilone, cabazitaxel, enfortumab vedotin, trastuzumab emtansine, tirbanibulin.
  • microtuial inhibitors are Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT plant alkaloids.
  • the plant alkaloid is a taxane (taxol, paclitaxel and docetaxel), a vinca alkaloid (vinblastine, vincristine, vindesine and vinorelbine), colchicine, podophylotoxin, or abraxane (protein-bound paclitaxel).
  • the chemotherapeutic agent is paclitaxel. In some embodiments, the chemotherapeutic agent is an antimetabolite.
  • the antimetabolite is 5-fluorouracil (5-FU), capecitabine, floxuridine, cytarabine, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, cytosine arabinoside, 5-azacytidine, gemcitabine, clofarabine, mercaptopurine, thioguanine, azathioprine, pentostatin, erythrohydroxynonyladenine, fludarabine, cladribine decitabine, Azacitidine, vidaza, or methotrexate.
  • the antimetabolite is cladribine.
  • the antimetabolite is clofarabine.
  • the antimetabolite is cytarabine. In an embodiment, the antimetabolite is gemcitabine. In an embodiment, the antimetabolite is floxuridine.
  • the chemotherapeutic agent is an antitumor antibiotic. In some embodiments, the antitumor antibiotic is bleomycin, dactinomycin, or mitomycin. In some embodiments, the antitumor antibiotic is daunorubicin, doxorubicin, doxil, epirubicin, idarubicin, mitoxantrone, or valrubicin. In some embodiments, the chemotherapeutic agent is a corticosteroid.
  • the corticosteroid is prednisone, methylprednisolone, or dexamethasone.
  • the additional therapeutic agent is a cel cycle checkpoint inhibitor.
  • the cel cycle checkpoint inhibitor is KU60019, AZD0156, Ceralasertib, Camonsertib, VE821, AZD7762, SRA737, Rabusertib, Prexasertib, SCH900776, or Adavosertib.
  • the cel cycle checkpoint inhibitor is KU60019.
  • the cel cycle checkpoint inhibitor is AZD0156.
  • the cel cycle checkpoint inhibitor is ceralasertib. In some embodiments, the cel cycle checkpoint inhibitor is camonsertib. In some embodiments, the cel cycle checkpoint inhibitor is VE821. In some embodiments, the cel cycle checkpoint inhibitor is AZD7762. In some embodiments, the cel cycle checkpoint inhibitor is SRA737. In some embodiments, the cel cycle checkpoint inhibitor is rabusertib. In some embodiments, the cel cycle checkpoint inhibitor is prexasertib. In some embodiments, the cel cycle checkpoint inhibitor is SCH900776. In some embodiments, the cel cycle checkpoint inhibitor is adavosertib.
  • the additional therapeutic agent is an immune check point inhibitor.
  • the immune checkpoint inhibitor is a PD-1/PD-L1 inhibitor, a LAG-3 inhibitor, a CTLA-4 inhibitor, a BTLA inhibitor, a TIM-3 inhibitor, or a TIGIT inhibitor.
  • the PD-1/PD-L1 inhibitor is a PD-1 inhibitor.
  • the PD-1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, or atezolizumab.
  • the PD-1 inhibitor is nivolumab.
  • the PD-1 inhibitor is pembrolizumab.
  • the PD-1 inhibitor is cemiplimab.
  • the PD-1 inhibitor is dostarlimab.
  • the PD- 1 inhibitor is zimberelimab.
  • the PD-1 inhibitor is retifanlimab.
  • the PD-1 inhibitor is atezolizumab.
  • PD-1/PD-L1 inhibitor is a PD-L1 inhibitor.
  • the PD-L1 inhibitor is avelumab, atezolizumab, or durvalumab.
  • the PD-L1 inhibitor is avelumab.
  • the PD-L1 inhibitor is atezolizumab.
  • the PD-L1 inhibitor is durvalumab.
  • the immune checkpoint inhibitor is a LAG-3 inhibitor.
  • the LAG-3 inhibitor is relatlimab.
  • the immune checkpoint inhibitor is a CTLA-4 inhibitor.
  • the immune checkpoint inhibitor is a BTLA inhibitor. In some embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is sabatolimab, TSR-022 (NCT02817633), MBG453 (NCT02608268), or LY3321367 (NCT03099109). In some embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor.
  • the TIM-3 inhibitor is sabatolimab, TSR-022 (NCT02817633), MBG453 (NCT02608268), or LY3321367 (NCT03099109).
  • the TIM-3 inhibitor is sabatolimab.
  • the immune checkpoint inhibitor is a TIM-3 inhibitor.
  • the TIM-3 inhibitor is TSR-022 (NCT02817633).
  • the TIM-3 inhibitor is MBG453 (NCT02608268).
  • the TIM-3 inhibitor is LY3321367 (NCT03099109).
  • the immune checkpoint inhibitor is a TIGIT inhibitor.
  • the TIGIT inhibitor is tiragolumab, domvanalimab, vibostolimab, etigilimab, M6223, or ociperlimab. In some embodiments, the TIGIT inhibitor is tiragolumab. In some embodiments, the TIGIT inhibitor is domvanalimab. In some embodiments, the TIGIT inhibitor is vibostolimab. In some embodiments, the TIGIT inhibitor is etigilimab. In some embodiments, the TIGIT inhibitor is M6223. In some embodiments, the TIGIT inhibitor is ociperlimab. Mintz Docket No.052326-573001WO IDY Ref.
  • the additional therapeutic agent is a BCL-2 inhibitor.
  • the BCL-2 inhibitor is venetoclax, navitoclax, oblimersen, obatoclax mesylate, AT-101, subatoclax, maritoclax, gossypol, apogossypol, TW-37, UMI-77, or BDA-366.
  • Anti-CD20 therapeutic agents In some embodiments, the additional therapeutic agent is an anti-CD20 therapeutic agent.
  • the anti-CD20 therapeutic agent is rituximab, arzerra, gazyva, ibritumomab tiuxetan, obinutuzumab, ofatumumab, riabni, rituxan, ruxience, truxima, zevalin, or tositumomab.
  • the additional therapeutic agent is a hormonal therapeutic agent.
  • the hormonal therapeutic agent is anastrozole, exemestand, letrozole, zoladex, lupon eligard, tamoxifen, raloxifene, goserelin, leuprorelin, fulvestrant, 4- hydroxytamoxifen, trioxifene, keoxifene, onapristone, toremifene; flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, or goserelin.
  • the additional therapeutic agent is a PARP inhibitor.
  • the PARP inhibitor is niraparib, rucaparib, olaparib, talazoparib, or veliparib.
  • the PARP inhibitor is niraparib, rucaparib, olaparib, saruparib, talazoparib, or veliparib.
  • MAT2A Inhibitors In some embodiments, the additional therapeutic agent is a MAT2A inhibitor. In some embodiments, the MAT2A inhibitor is AG- (Compound 8), or Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT (Compound 8).
  • the MAT2A (Compound 8) or a pharmaceuticaly acceptable salt the MAT2A inhibitor is a compound disclosed in is incorporated herein by reference for al purposes.
  • the MAT2A inhibitor is a compound disclosed in WO2018/045071, the content of which is incorporated herein by reference for al purposes.
  • Radiotherapy In some embodiments, the additional therapeutic agent is radiation therapy.
  • VEGF Inhibitors In some embodiments, the additional therapeutic agent is a VEGF inhibitor.
  • the VEGF inhibitor is Bevacizumab, aflibercept, ranibizumab, sorafenib, dasatinib, sunitinib, nilotinib, pazopanib, pegaptanib, axitinib, lenvatinib, ramucirumab, or regorafenib.
  • the additional therapeutic agent is a tyrosine kinase inhibitor.
  • the tyrosine kinase inhibitor is afatinib, cetuximab, imatinib, trastuzumab, gefitinib, dacomitinib, osimertinib, neratinib, almonertinib, brigatinib, icotinib, olmutinib, sorafenib, dasatinib, bosutinib, ponatinib, asciminib, sunitinib, erlotinib, nilotinib, lapatinib, tucatinib, pyrotinib, panitumumab, nimotuzumab, necitumumab, mobocertinib, vandetanib, lenvatinib, pazopanib, mubritinib, fostamatinib, calquence, pertu
  • the additional therapeutic agent is an mTOR inhibitor.
  • the mTOR inhibitor is rapamycin, everolimus, sirolimus, or temsirolimus.
  • AKT Inhibitors In some embodiments, the additional therapeutic agent is an ATK inhibitor.
  • the ATK inhibitor is ipatasertib, mk-2206, perifosine, capivasertib, triciribine, or GSK690693.
  • the additional therapeutic agent is a CDK inhibitor.
  • the CDK inhibitor is flavopiridol, roscovitine, RO-3306, dinaciclib, milciclib, palbociclib, ribociclib, abemaciclib, BS-181, DRB, meriolin 3, variolin b, meridianin e, nortopsentins, AZD5438, roniciclib, SNS-032, sorafenib, K03861, THZ531, THZ1, E9, SY- 1365, or seliciclib.
  • the CDK inhibitor is palbociclib, ribociclib, or abemaciclib.
  • the additional therapeutic agent is a PI3K inhibitor.
  • the PI3K inhibitor is idelalisib, alpelisib, leniolisib, duvelisib, or copanlisib.
  • JAK Inhibitors In some embodiments, the additional therapeutic agent is a JAK inhibitor. In some embodiments, the JAK inhibitor is tofacitinib, baricitinib, ruxolitinib, upadacitinib, fedratinib, filgotinib, or abrocitinib.
  • the additional therapeutic agent is an inhibitor of cereblon.
  • the inhibitor of cereblon is thalidomide or lenalidomide.
  • MAPK/ERK Inhibitors In some embodiments, the additional therapeutic agent is a MAPK/ERK inhibitor.
  • the MAPK/ERK inhibitor is vemurafenib, dabrafenib, octreotide, pasireotide, SB590885, GDC0879, LGX818, AZ628, RAF709, binimetinib, L-778, MK2206, Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT pimasertib, rafametinib, salirasib, selumetinib, SML-8-731, tipifarnib, lonafarnib, trametinib, ulixertinib, WX-554, or cobimetinib.
  • the additional therapeutic agent is a Wnt/ ⁇ -catenin inhibitor.
  • the Wnt/ ⁇ -catenin inhibitor is capmatinib, resibufogenin, or isoquercitrin.
  • Proteosome Inhibitors In some embodiments, the additional therapeutic agent is a proteosome inhibitor. In some embodiments, the proteosome inhibitor bortezomib, carfilzomib, or ixazomib.
  • Histone Deacetylase Inhibitors In some embodiments, the additional therapeutic agent is a histone deacetylase inhibitor.
  • the histone deacetylase inhibitor is vorinostat, romidepsin, panobinostat, or belinostat.
  • the additional therapeutic agent is a recombinant IL-2.
  • the recombinant IL-2 is aldesleukin.
  • RANKL Inhibitors In some embodiments, the additional therapeutic agent is a RANKL inhibitor. In some embodiments, the RANKL inhibitor is Denosumab or AS2676293.
  • B4GALNT1 Inhibitors In some embodiments, the additional therapeutic agent is a B4GALNT1 inhibitor.
  • the B4GALNT1 inhibitor is Dinutuximab.
  • the additional therapeutic agent is a SLAMF7 inhibitor.
  • the SLAMF7 inhibitor is elotuzumab.
  • the additional therapeutic agent is a IDH2/IDH1 inhibitor.
  • the IDH2/IDH1 inhibitor is enasidenib, ivosidenib, AGI-6780, AG-221, FT-2102, IDH305, GSK 321, or BAY1436032.
  • the additional therapeutic agent is a BTK inhibitor.
  • the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib.
  • FLT3 Inhibitors In some embodiments, the additional therapeutic agent is a FLT3 inhibitor. In some embodiments, the FLT3 inhibitor is sunitinib, midostaurin, lestaurtinib, KW-2449, crenolanib, or gilteritinib.
  • PDGFR ⁇ Inhibitors In some embodiments, the additional therapeutic agent is a PDGFR ⁇ inhibitor.
  • the PDGFR ⁇ inhibitor is olaratumab, avapritinib, ayvakit, imatinib, ripretinib, or regorafenib.
  • the additional therapeutic agent is a smoothened inhibitor.
  • the smoothened inhibitor is sonidegib, itraconazole, or glasdegib.
  • the additional therapeutic agent is a LHRH antagonist or LHRH agonist.
  • the LHRH antagonist or LHRH agonist is goserelin, leuprorelin or buserelin.
  • the additional therapeutic agent is a cel based therapy.
  • the cel based therapy is tumor-infiltrating lymphocyte (TIL) therapy; engineered t cel receptor (TCR) therapy; chimeric antigen receptor (CAR) T cel therapy; Natural Kiler (NK) cel therapy; or sipuleucel-T.
  • TIL tumor-infiltrating lymphocyte
  • TCR engineered t cel receptor
  • CAR chimeric antigen receptor
  • NK Natural Kiler
  • sipuleucel-T xxxii) OX40 Inhibitors Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT
  • the additional therapeutic agent is a OX40 inhibitor.
  • the OX40 inhibitor is ivuxolimab, cudarolimab, utomilumab, or INBRX-106.
  • 41BB (CD137) Inhibitors In some embodiments, the additional therapeutic agent is a 41BB (CD137) inhibitor. In some embodiments, the 41BB (CD137) inhibitor is urelumab.
  • VISTA Inhibitors In some embodiments, the additional therapeutic agent is a VISTA inhibitor. In some embodiments, the VISTA inhibitor is hmbd-002.
  • CD96 Inhibitors In some embodiments, the additional therapeutic agent is a CD96 inhibitor. In some embodiments, the CD96 inhibitor is GSK6097608.
  • the additional therapeutic agent is a TGF ⁇ inhibitor.
  • the TGF ⁇ inhibitor is SAR-439459.
  • CD19 Inhibitors In some embodiments, the additional therapeutic agent is a CD19 inhibitor. In some embodiments, the CD19 inhibitor is tafasitamab, loncastuximab tesirine, or blinatumomab.
  • xxxix CD30 Inhibitors In some embodiments, the additional therapeutic agent is a CD30 inhibitor. In some embodiments, the CD30 inhibitor is brentuximab, vedotin, SGN-30, or MDX-060.
  • the additional therapeutic agent is a CD38 inhibitor.
  • the CD38 inhibitor is daratumumab, darzalex, isatuximab, or sarclisa.
  • xli) CD39 Inhibitors In some embodiments, the additional therapeutic agent is a CD39 inhibitor. In some embodiments, the CD39 inhibitor is pur001, ES002023, TTX-030, IPH5201, or SRF617. Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT xli) CD52 Inhibitors In some embodiments, the additional therapeutic agent is a CD52 inhibitor.
  • the CD52 inhibitor is alemtuzumab.
  • xlii) CD73 Inhibitors In some embodiments, the additional therapeutic agent is a CD73 inhibitor. In some embodiments, the CD73 inhibitor is oleclumab, PSB-12379, OP-5244, AB-680, CD73-IN-3, MethADP triammonium, dalutrafusp alfa, BK50164, mupadolimab, uliledlimab, MRS4620, BMS-986179, NZV930, AK119, SYM024, INCA00186, or ORIC-533. xliv) A2AR Inhibitors In some embodiments, the additional therapeutic agent is an A2AR inhibitor.
  • the A2AR inhibitor is istradefyline, vipadenant, CVT-6883, enprofyline, ciforadenant, imaradenant, etrumadenant, NIR178, EOS100850, CS3005, PBF-999, or INCB106385.
  • the additional therapeutic agent is an A2BR inhibitor.
  • the A2BR inhibitor is pbf-1129, QAF805, LAS101057 AB928, ISAM140, or TT- 4.
  • IDO1 & TDO2 Inhibitors In some embodiments, the additional therapeutic agent is an IDO1 or a TDO2 inhibitor.
  • the IDO1 or TDO2 inhibitor is Indoximod, Epacadostat, Navoximod, PF-06840003, BGS-5777, BMS-986205, LW106, IOM2983, RG-70099, LY- 3381916, NLG-802, or LPM-3480226.
  • Arginase Inhibitors In some embodiments, the additional therapeutic agent is an arginase inhibitor. In some embodiments, the arginase inhibitor is numidargistat, pegzilarginase, or INCB001158. xlvii) B7-H3 Inhibitors In some embodiments, the additional therapeutic agent is a B7-H3 inhibitor.
  • the B7-H3 inhibitor is enoblituzumab, I-Omburtamab, DS-7300, or MGC018. Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT xlix) B7-H4 Inhibitors
  • the additional therapeutic agent is a B7-H4 inhibitor.
  • the B7-H4 inhibitor is mt-1660, FPA150, or AZD8205.
  • PRMT5 Inhibitors In some embodiments, the additional therapeutic agent is a PRMT5 inhibitor. In some embodiments, the PRMT5 inhibitor is a MTA-cooperative PRMT5 inhibitor.
  • the PRMT5 inhibitor is a compound having the structure: or a pharmaceuticaly In some or a pharmaceuticaly In some embodiments, the PRMT5 inhibitor is: or a pharmaceuticaly acceptable In an embodiment, the PRMT5 inhibitor is Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT or a pharmaceuticaly acceptable salt thereof. In an embodiment, the PRMT5 inhibitor is or a pharmaceuticaly In an embodiment, or a pharmaceuticaly acceptable salt thereof. In an embodiment, the PRMT5 inhibitor is TNG462 or a pharmaceuticaly acceptable salt thereof. In an embodiment, the PRMT5 inhibitor is TNG908 or a pharmaceuticaly acceptable salt thereof.
  • the PRMT5 inhibitor is AZD3470 or a pharmaceuticaly acceptable salt thereof.
  • Additional PRMT5 inhibitors can include those described in WO2022/026892, WO2021/086879, WO2021/050915, and WO2023/036974, the contents of each are incorporated herein by reference in their entirety.
  • PTK7 inhibitors In some embodiments, the additional therapeutic agent is a PTK7 inhibitor.
  • ADC Antibody Drug Conjugates
  • ADC Antibody Drug Conjugates
  • ADC Antibody Drug Conjugates
  • ADC Antibody Drug Conjugates
  • ADC Antibody Drug Conjugates
  • ADC Antibody Drug Conjugates
  • ADC Antibody Drug Conjugates
  • ADC Antibody Drug Conjugates
  • ADC Antibody Drug Conjugates
  • ADC Antibody Drug Conjugates
  • ADC Antibody Drug Conjugates
  • ADC antibody drug conjugates
  • the antibody is a bispecific antibody.
  • ADC antibody drug conjugates
  • the antitumor compound is an additional therapeutic agent disclosed herein.
  • the antitumor compound is a chemotherapeutic agent disclosed herein.
  • the disclosure also provides antibody drug conjugates (ADC) comprising at least two antitumor compounds conjugated to an antibody via a linker.
  • ADC antibody drug conjugates
  • the at least two antitumor compounds are selected from a PARG inhibitor disclosed herein and one or more additional therapeutic agents disclosed herein.
  • the at least two antitumor compounds are selected from the additional therapeutic agents disclosed herein.
  • the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is a compound of Formula I.
  • the antitumor compound is a PARG inhibitor, Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT wherein the PARG inhibitor is Compound 1.
  • the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is Compound 11.
  • ADC antibody drug conjugates
  • the additional therapeutic agent is an agent described herein. In an embodiment, the additional therapeutic agent is gemcitabine. In an embodiment, the additional therapeutic agent is paclitaxel. In an embodiment, the additional therapeutic agent is Ku60019. In an embodiment, the additional therapeutic agent is AZD0156. In an embodiment, the additional therapeutic agent is ceralasertib. In an embodiment, the additional therapeutic agent is camonsertib. In an embodiment, the additional therapeutic agent is VE821. In an embodiment, the additional therapeutic agent is AZD6672. In an embodiment, the additional therapeutic agent is SRA737. In an embodiment, the additional therapeutic agent is rabusertib. In an embodiment, the additional therapeutic agent is prexasertib.
  • the additional therapeutic agent is SCH900776. In an embodiment, the additional therapeutic agent is adavosertib. In an embodiment, the additional therapeutic agent is cladribine. In an embodiment, the additional therapeutic agent is clofarabine. In an embodiment, the additional therapeutic agent is cytarabine. In an embodiment, the additional therapeutic agent is floxuridine. In an embodiment, the additional therapeutic agent is raloxifene. In an embodiment, the additional therapeutic agent is mechlorethamine. In an embodiment, the additional therapeutic agent is perfosamide. In an embodiment, the additional therapeutic agent is carboplatin. In an embodiment, the additional therapeutic agent is cisplatin. In an embodiment, the additional therapeutic agent is satraplatin.
  • the additional therapeutic agent is nivolumab. In an embodiment, the additional therapeutic agent is pembrolizumab. In an embodiment, the additional therapeutic agent is cemiplimab. In an embodiment, the additional therapeutic agent is dostarlimab. In an embodiment, the additional therapeutic agent is zimberelimab. In an embodiment, the additional therapeutic agent is retifanlimab. In an embodiment, the additional therapeutic agent is atezolizumab. In an embodiment, the additional therapeutic agent is avelumab. In an embodiment, the additional therapeutic agent is atezolizumab. In an embodiment, the additional therapeutic agent is durvalumab.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and an additional therapeutic agent.
  • the additional therapeutic agent is an agent described herein. In some embodiments, the additional therapeutic agent is listed above.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and gemcitabine or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and paclitaxel or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and Ku60019 or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and AZD0156 or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and ceralasertib or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and camonsertib or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and VE821 or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and AZD6672 or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and SRA737 or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and rabusertib or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and prexasertib or a pharmaceuticaly acceptable salt thereof.
  • Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT In another aspect, provided herein is a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and SCH900776 or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and adavosertib or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and cladribine or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and clofarabine or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and cytarabine or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and floxuridine or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and raloxifene or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and mechlorethamine or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and perfosamide or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and carboplatin or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and cisplatin or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and satraplatin or a pharmaceuticaly acceptable salt thereof. Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and nivolumab or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and pembrolizumab or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and cemiplimab or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and dostarlimab or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and zimberelimab or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and retifanlimab or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and atezolizumab or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and avelumab or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and atezolizumab or a pharmaceuticaly acceptable salt thereof.
  • a combination product comprising Compound 1 or a pharmaceuticaly acceptable salt thereof, and durvalumab or a pharmaceuticaly acceptable salt thereof.
  • the administration of a pharmaceutical combination provided herein may result in a beneficial effect, e.g. a synergistic therapeutic effect, e.g., with regard to aleviating, delaying progression of or inhibiting the symptoms, and may also result in further surprising beneficial effects, e.g., fewer side-efects, an improved quality of life or a decreased morbidity, compared with a monotherapy applying only one of the pharmaceuticaly active ingredients used in the combination of the disclosure.
  • No.2023-029-D-PCT Methods of Treatment is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeuticaly effete amount of a PARG inhibitor and administering to the subject a therapeuticaly effete amount of an additional therapeutic agent, thereby treating the cancer in the subject.
  • methods of treating cancer in a subject in need thereof the methods comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent, together with at least a pharmaceuticaly acceptable carrier, thereby treating the cancer in the subject.
  • a homologous recombinant deficient (HRD) cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent, thereby treating the cancer in the subject.
  • methods of treating and/or preventing a homologous recombinant deficient (HRD) cancer in a subject in need thereof the methods comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent together with at least a pharmaceuticaly acceptable carier, thereby treating the cancer in the subject.
  • the HRD cancer is breast cancer.
  • the HRD cancer is ovarian cancer.
  • methods of treating and/or preventing a cancer in a subject in need thereof comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent, thereby treating the cancer in the subject, wherein the cancer is homologous recombinant deficient (HRD) cancer and is Estrogen Receptor (ER) positive.
  • methods of treating and/or preventing a cancer in a subject in need thereof comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent, thereby treating the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, and is optionaly Progesterone Receptor (PR) positive.
  • HRD homologous recombinant deficient
  • ER Estrogen Receptor
  • methods of treating and/or preventing a cancer in a subject in need thereof comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent, thereby treating the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, and is optionaly human epidermal growth factor receptor 2 (HER2) negative.
  • HRD cancer is ER positive, and is optionaly human epidermal growth factor receptor 2 (HER2) negative.
  • HER2 human epidermal growth factor receptor 2
  • No.2023-029-D-PCT In an embodiment are methods of treating and/or preventing a cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent, thereby treating the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, is optionaly PR positive, and is optionaly HER2 negative.
  • the cancer is breast cancer or ovarian cancer.
  • the methods comprising administering to the subject a combination comprising a PARG inhibitor and an additional therapeutic agent, thereby treating the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, is optionaly PR positive, and is optionaly HER2 negative.
  • the HRD cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-smal cel lung cancer (NSCLC), or prostate cancer.
  • the HRD cancer is breast cancer or ovarian cancer.
  • the HRD cancer is smal cel lung cancer, kidney cancer, renal cancer, urothelial cancer, melanoma, liver cancer, bladder cancer, stomach cancer, carcinoma, lymphoma, glioblastoma, sarcoma, leukemia, myeloma, or lymphoid malignancies.
  • the cancer is characterized by a reduction or absence of BRCA1 and/or BRCA2 gene expression, an absence or mutation of BRCA1 and/or BRCA2 genes, a reduced function of BRCA1 and/or BRCA2 proteins, or a combination thereof.
  • the cancer is characterized by microsatelite instability- high (MSI-H).
  • the cancer is characterized by microsatelite stable (MSS).
  • MSS microsatelite stable
  • a method of treating cancer in a subject in need thereof comprising (a) obtaining a biological sample from the subject; (b) determining if the biological sample is i) a homologous recombination deficient (HRD) cancer; i) an ER positive cancer; ii) a PR positive cancer; iv) a HER2 negative cancer; v) a cancer characterized by a reduction or absence of BRCA1 and/or BRCA2 gene expression, an absence or mutation of BRCA1 and/or BRCA2 genes, a reduced function of BRCA1 and/or BRCA2 proteins, or a combination thereof; Mintz Docket No.052326-573001WO IDY Ref.
  • No.2023-029-D-PCT vi) microsatelite instability-high (MSI-H), microsatelite instability-low (MSI-L), or microsatelite stable (MSS); or vi) any combination of i) to vi); and (c) administering to the subject a therapeuticaly effete amount of a Poly ADP-ribose glycohydrolase (PARG) inhibitor and therapeuticaly effete amount of an additional therapeutic agent if the biological sample is i) a homologous recombination deficient (HRD) cancer; i) an ER positive cancer; ii) a PR positive cancer; iv) a HER2 negative cancer; v) a cancer characterized by a reduction or absence of BRCA1 and/or BRCA2 gene expression, the absence or mutation of BRCA1 and/or BRCA2 genes, or reduced function of BRCA1 and/or BRCA2 proteins, or combination thereof; vi) microsatelite instability-high (MSI-H) or microsatelite stable (MSS);
  • the biological sample is tissue or blood. In an embodiment, the biological sample is tissue. In an embodiment, the biological sample is blood. In an embodiment, the blood is whole blood. In an embodiment, the blood is blood serum. In an embodiment, the blood is blood plasma. It is understood that methods of determining if a biological sample is a homologous recombination deficient (HRD) cancer, an ER positive cancer, a PR positive cancer, a HER2 negative cancer, a cancer characterized by a reduction or absence of BRCA1 and/or BRCA2 gene expression, the absence or mutation of BRCA1 and/or BRCA2 genes, or reduced function of BRCA1 and/or BRCA2 proteins, or combination thereof, or a microsatelite instability-high (MSI-H), microsatelite instability-low (MSI-L), or microsatelite stable (MSS) sample are known in the art.
  • HRD homologous recombination deficient
  • a biological sample is any one of i) to (vi) as defined and described herein or any combination thereof.
  • methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeuticaly effete amount of a pharmaceutical composition comprising a PARG inhibitor and a therapeuticaly effete amount of a pharmaceutical composition comprising an additional therapeutic agent, thereby treating the cancer in the subject.
  • Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT use of a combination of a PARG inhibitor and an additional therapeutic agent for the manufacture of a medicament is provided.
  • the PARG inhibitor is Compound 1.
  • the PARG inhibitor is Compound 1.
  • the additional therapeutic agent is an agent described herein. In some embodiments, the additional therapeutic agent is listed above.
  • use of a combination of a PARG inhibitor and an additional therapeutic agent for the treatment of cancer is provided.
  • the PARG inhibitor is a compound of Formula I.
  • the PARG inhibitor is Compound 1.
  • provided is a combination of Compound 1 and gemcitabine for the treatment of cancer.
  • provided is a combination of Compound 1 and paclitaxel for the treatment of cancer.
  • No.2023-029-D-PCT nivolumab for the treatment of cancer.
  • provided is a combination of Compound 1 and pembrolizumab for the treatment of cancer.
  • provided is a combination of Compound 1 and cemiplimab for the treatment of cancer.
  • provided is a combination of Compound 1 and dostarlimab for the treatment of cancer.
  • provided is a combination of Compound 1 and zimberelimab for the treatment of cancer.
  • provided is a combination of Compound 1 and retifanlimab for the treatment of cancer.
  • provided is a combination of Compound 1 and atezolizumab for the treatment of cancer.
  • the PARG inhibitor is a compound of Formula I: or a pharmaceuticaly acceptable salt thereof; wherein the variables are defined supra. In another embodiment, the PARG inhibitor is Compound 11, or a pharmaceuticaly acceptable salt thereof. In another embodiment, the PARG inhibitor is Compound 1, or a pharmaceuticaly acceptable salt thereof. In an embodiment, the additional therapeutic agent is selected from those listed above.
  • a product containing a PARG inhibitor and an additional therapeutic agent as a combination product for simultaneous, separate, or sequential use in medicine is a compound of Formula I.
  • the PARG inhibitor is Compound 1.
  • the additional therapeutic agent is selected from those listed above.
  • a product containing a PARG inhibitor and an additional therapeutic agent as a combination product for simultaneous, separate, or sequential use in treating cancer in a subject is provided.
  • the PARG inhibitor is a Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT compound of Formula I.
  • the PARG inhibitor is Compound 1.
  • the additional therapeutic agent is selected from those listed above.
  • the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, and esophageal cancer.
  • the cancer is ovarian, gastric, or breast cancer.
  • the cancer is lung, cervical or pancreatic cancer.
  • the cancer is prostate cancer.
  • the cancer is breast cancer.
  • the cancer is ovarian cancer.
  • the cancer is endometrial cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colorectal cancer.
  • the cancer is non-smal cel lung cancer (NSCLC).
  • the cancer is smal cel lung cancer.
  • the cancer is kidney cancer, renal cancer, urothelial cancer, melanoma, liver cancer, bladder cancer, stomach cancer, carcinoma, lymphoma, glioblastoma, sarcoma, leukemia, myeloma, or lymphoid malignancies.
  • the cancer is metastatic.
  • the disease or disorder is an advanced or metastatic solid tumor.
  • the cancer is a solid malignant tumor.
  • the PARG inhibitor and the additional therapeutic agent are in separate dosage forms. In another embodiment, the PARG inhibitor and the additional therapeutic agent are in the same dosage form.
  • the treatment comprises administering the PARG inhibitor, or a pharmaceuticaly acceptable salt thereof, and the additional therapeutic agent, or a pharmaceuticaly acceptable salt thereof, at substantialy the same time.
  • the treatment comprises administering the PARG inhibitor, or a pharmaceuticaly acceptable salt thereof, and the additional therapeutic agent, or a pharmaceuticaly acceptable salt thereof, at diferent times.
  • the PARG inhibitor, or a pharmaceuticaly acceptable salt thereof is administered to the subject, folowed by administration of the additional therapeutic agent, or a pharmaceuticaly acceptable salt thereof.
  • the additional therapeutic agent, or a pharmaceuticaly acceptable salt thereof is administered to the subject, folowed by administration of PARG inhibitor, or a pharmaceuticaly acceptable salt thereof.
  • the PARG inhibitor, or a pharmaceuticaly acceptable salt thereof, and the additional therapeutic agent, or a pharmaceuticaly acceptable salt thereof are administered oraly.
  • Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT is provided herein.
  • a PARG inhibitor, or a pharmaceuticaly acceptable salt thereof, and an additional therapeutic agent, or a pharmaceuticaly acceptable salt thereof, for use in therapy are for use in the treatment of cancer in a subject in need thereof.
  • the method involves the administration of a therapeuticaly effete amount of a combination or composition comprising compounds provided herein, or pharmaceuticaly acceptable salts thereof, to a subject (including, but not limited to a human or animal) in need of treatment (including a subject identified as in need).
  • the treatment includes co-administering the amount of the PARG inhibitor, or a pharmaceuticaly acceptable salt thereof, and the amount of the additional therapeutic agent, or a pharmaceuticaly acceptable salt thereof.
  • the amount of the PARG inhibitor or a pharmaceuticaly acceptable salt thereof and the amount of the additional therapeutic agent or a pharmaceuticaly acceptable salt thereof are in a single formulation or unit dosage form.
  • the amount of PARG inhibitor or a pharmaceuticaly acceptable salt thereof and the amount of additional therapeutic agent or a pharmaceuticaly acceptable salt thereof are in separate formulations or unit dosage forms.
  • the treatment can include administering the amount of a PARG inhibitor or a pharmaceuticaly acceptable salt thereof and the amount of an additional therapeutic agent or a pharmaceuticaly acceptable salt thereof at substantialy the same time or administering the amount of PARG inhibitor or a pharmaceuticaly acceptable salt thereof and the amount of an additional therapeutic agent or a pharmaceuticaly acceptable salt thereof at diferent times.
  • the amount of PARG inhibitor or a pharmaceuticaly acceptable salt thereof and/or the amount of additional therapeutic agent or a pharmaceuticaly acceptable salt thereof is administered at dosages that would not be efective when either of PARG inhibitor or a pharmaceuticaly acceptable salt thereof, or additional therapeutic agent or a pharmaceuticaly acceptable salt thereof is administered alone, but which amounts are effete in combination.
  • the treatment includes co-administering the amount of Compound 1, or a pharmaceuticaly acceptable salt thereof, and the amount of the additional therapeutic agent listed herein.
  • the amount of Compound 1 or a pharmaceuticaly acceptable salt thereof and the amount of the additional therapeutic agent listed herein are in a single formulation or unit dosage form.
  • the amount of Compound 1 or a pharmaceuticaly acceptable salt thereof and the amount of Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT the additional therapeutic agent listed herein are in separate formulations or unit dosage forms.
  • the treatment can include administering the amount of Compound 1 or a pharmaceuticaly acceptable salt thereof and the amount of the additional therapeutic agent listed herein at substantialy the same time or administering the amount of Compound 1 or a pharmaceuticaly acceptable salt thereof and the amount of the additional therapeutic agent listed herein at diferent times.
  • the amount of Compound 1 or a pharmaceuticaly acceptable salt thereof and/or the amount of the additional therapeutic agent listed herein is administered at dosages that would not be efective when one or both of Compound 1 or a pharmaceuticaly acceptable salt thereof and the additional therapeutic agent listed herein is administered alone, but which amounts are effete in combination.
  • Non-Limiting Exemplary Embodiments In further embodiments 1 to 201 below, the present disclosure includes: 1. In an embodiment 1, provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeuticaly effete amount of a Poly ADP-ribose glycohydrolase (PARG) inhibitor and administering to the subject a therapeuticaly effete amount of an additional therapeutic agent. 2.
  • PARG Poly ADP-ribose glycohydrolase
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeuticaly effete amount of a Poly ADP-ribose glycohydrolase (PARG) inhibitor, wherein the subject is concurrently receiving an additional therapeutic agent.
  • PARG Poly ADP-ribose glycohydrolase
  • R1 is selected from the group consisting of cyano, C1-2alkyl, and C1-2haloalkyl
  • Ar is a 5-membered heteroaryl
  • X2 is CH or CF
  • R2 is selected from the group consisting of C1-3alkyl, C1-3haloalkyl, hydroxyC1-3alkyl, and cyano
  • ring B is 5- or 6-membered heterocycloalkyl substituted with Ra, Rb, and Rc
  • Ra is hydrogen, C alkyl, C haloalkyl, halo, h d d 1-4 1-4 ydroxy, or -C(O)R (where R is hydrogen, C1-6alkyl, or C1-6haloalkyl); and Rb and Rc are independently selected from
  • R1 is selected from the group consisting of cyano, C1-2alkyl, and C1-2haloalkyl
  • Ar is a 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl
  • X2 is CH or CF
  • R2 is selected from the group consisting of C1-3haloalkyl, C1-3alkyl, hydroxyC1-3alkyl, and cyano
  • ring B is 5- or 6-membered heterocycloalkyl substituted with Ra, Rb, and Rc
  • Ra is hydrogen, C alky d d 1-4 l, C1-4haloalkyl, halo, hydroxy, or -C(O)R (where R is hydrogen, C1-6alkyl, or C1-6haloalkyl); and
  • Rb and Rc are independently selected from C1-6alkyl, hydrogen, hydroxy, C1-6alkoxy, halo, C1-6haloalkyl, and C1-6haloalkoxy.
  • Ra is hydrogen, C d d 1-4alkyl, C1-4haloalkyl, halo, hydroxy, or -C(O)R (where R is hydrogen, C1-6alkyl, or C1-6haloalkyl); and Rb and Rc are independently selected from hydrogen, C1-6alkyl, hydroxy, C1-6alkoxy, halo, C1-6haloalkyl, and C1-6haloalkoxy.
  • Ra is hydrogen, C1-4alkyl, or C1-4haloalkyl; and Rb and Rc are independently selected from hydrogen and C1-6alkyl.
  • 21 provided is the method of any one of embodiments 4 to 17, wherein Ra is hydrogen, C1-4alkyl, or C1-4haloalkyl; and Rb and Rc are independently selected from C1-6alkyl and hydrogen.
  • 22 provided is the method of any one of embodiments 4 to 17, wherein Ra is hydrogen; Rb and Rc are each independently C1-6 alkyl or hydrogen.
  • the PARG inhibitor is Compound 11 or a pharmaceuticaly acceptable salt thereof.
  • the PARG inhibitor is Compound 1 or a pharmaceuticaly acceptable salt thereof.
  • the additional therapeutic agent is an agent described herein.
  • the additional therapeutic agent is a chemotherapeutic agent, a cel cycle checkpoint inhibitor, or an immune checkpoint inhibitor.
  • 27 provided is the method of any one of embodiments 4 to 24, wherein the additional therapeutic agent is a chemotherapeutic agent.
  • 28 provided is the method of any one of embodiments 4 to 24, wherein the additional therapeutic agent is a cel cycle checkpoint inhibitor. 29.
  • the additional therapeutic agent is an immune checkpoint inhibitor.
  • the additional therapeutic agent is a MAT2A inhibitor.
  • 31 provided is the method of embodiment 27, wherein the chemotherapeutic agent is an alkylating agent.
  • 32 provided is the method of embodiment 27, wherein the chemotherapeutic agent is a microtubule inhibitor. Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT 33.
  • the chemotherapeutic agent is an antimetabolite. 34.
  • chemotherapeutic agent is gemcitabine, paclitaxel, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, or satraplatin.
  • the cel cycle checkpoint inhibitor is Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, or adavosertib.
  • the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab. 37.
  • the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, satraplatin, nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonser
  • the additional therapeutic agent is gemcitabine, carboplatin, or paclitaxel.
  • the MAT2A inhibitor is compound 8.
  • the cancer is a homologous recombination deficient (HRD) cancer.
  • HRD homologous recombination deficient
  • the cancer is characterized by a reduction or absence of BRCA2 gene expression, an absence or mutation of BRCA2 genes, or a reduced function of BRCA2 proteins.
  • the cancer is ER positive.
  • the cancer is PR positive.
  • the method of any one of embodiments 1 to 44, wherein the cancer is HER2 negative. 46.
  • any one of embodiments 1 to 45 wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-smal cel lung cancer (NSCLC), or prostate cancer.
  • the cancer is breast cancer or ovarian cancer.
  • the PARG inhibitor and the additional therapeutic agent are in separate dosage forms.
  • the PARG inhibitor and the additional therapeutic agent are in the same dosage form. 50.
  • a combination product comprising a PARG inhibitor, or a pharmaceuticaly acceptable salt thereof, and an additional therapeutic agent, or a pharmaceuticaly acceptable salt thereof.
  • the PARG inhibitor of embodiment 50 is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof.
  • the PARG inhibitor of embodiment 51 is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof as defined in any one of embodiments 4- 22. 53.
  • the PARG inhibitor of embodiment 50 or 51 is Compound 1 or a pharmaceuticaly acceptable salt thereof.
  • the PARG inhibitor of embodiment 50 or 51 is Compound 1. 55.
  • the additional therapeutic agent of any one of embodiments 50 to 54 is an additional therapeutic agent described herein.
  • the additional therapeutic agent of any one of embodiments 50 to 54 is a chemotherapeutic agent, a cel cycle checkpoint inhibitor, or an immune checkpoint inhibitor.
  • the additional therapeutic agent is a chemotherapeutic agent.
  • the additional therapeutic agent is a chemotherapeutic agent.
  • the additional therapeutic agent is a cel cycle checkpoint inhibitor.
  • the additional therapeutic agent is an immune checkpoint inhibitor. 60.
  • 61 provided is the combination product of embodiment 57, wherein the chemotherapeutic agent is an alkylating agent.
  • the chemotherapeutic agent is a microtubule inhibitor.
  • 63 provided is the combination product of embodiment 57, wherein the chemotherapeutic agent is an antimetabolite. 64.
  • chemotherapeutic agent is gemcitabine, paclitaxel, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, or satraplatin.
  • the cel cycle checkpoint inhibitor is Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, or adavosertib.
  • embodiment 66 provided is the combination product of embodiment 59, wherein the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab. 67.
  • embodiment 67 provided is the combination product of embodiment 56, wherein the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, Mintz Docket No.052326-573001WO IDY Ref.
  • the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib,
  • No.2023-029-D-PCT cisplatin, satraplatin, nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • 68 provided is the combination product of embodiment 67, wherein the additional therapeutic agent is gemcitabine, carboplatin, or paclitaxel.
  • 69 provided is the combination product of embodiment 60, wherein the MAT2A inhibitor is compound 8. 70.
  • the additional therapeutic agent of embodiment 56 is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, satraplatin, nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the additional therapeutic agent of embodiment 70 is gemcitabine, carboplatin, or paclitaxel.
  • a combination product comprising a first pharmaceutical composition comprising a therapeuticaly effete amount of a PARG inhibitor and a second pharmaceutical composition comprising a therapeuticaly effete amount of an additional therapeutic agent.
  • the PARG inhibitor of embodiment 72 is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof.
  • the PARG inhibitor of embodiment 73 is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof as defined in any one of embodiments 4- 22. 75.
  • the PARG inhibitor of embodiment 72 or 73 is Compound 11, or a pharmaceuticaly acceptable salt thereof. 76. In embodiment 76, the PARG inhibitor of embodiment 72 or 73 is Compound 1, or a pharmaceuticaly acceptable salt thereof. 77. In embodiment 77, the additional therapeutic agent of any one of embodiments 72 to 76 is an additional therapeutic agent described herein. Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT 78. In embodiment 78, the additional therapeutic agent of any one of embodiments 72 to 76 is a chemotherapeutic agent, a cel cycle checkpoint inhibitor, or an immune checkpoint inhibitor. 79.
  • the additional therapeutic agent is a chemotherapeutic agent.
  • 80 provided is the combination product of any one of embodiments 72 to 76, wherein the additional therapeutic agent is a cel cycle checkpoint inhibitor.
  • 81 provided is the combination product of any one of embodiments 72 to 76, wherein the additional therapeutic agent is an immune checkpoint inhibitor.
  • 82 provided is the combination product of any one of embodiments 72 to 76, wherein the additional therapeutic agent is a MAT2A inhibitor.
  • 83 provided is the combination product of embodiment 79, wherein the chemotherapeutic agent is an alkylating agent.
  • chemotherapeutic agent is a microtubule inhibitor.
  • the chemotherapeutic agent is an antimetabolite.
  • the chemotherapeutic agent is gemcitabine, paclitaxel, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, or satraplatin. 87.
  • embodiment 87 provided is the combination product of embodiment 80, wherein the cel cycle checkpoint inhibitor is Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, or adavosertib. 88.
  • embodiment 88 provided is the combination product of embodiment 81, wherein the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • embodiment 89 provided is the combination product of embodiment 78, wherein the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, Mintz Docket No.052326-573001WO IDY Ref.
  • the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib,
  • the additional therapeutic agent is gemcitabine, carboplatin, or paclitaxel.
  • MAT2A inhibitor is compound 8. 92.
  • the additional therapeutic agent of embodiment 78 is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, satraplatin, nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the additional therapeutic agent of embodiment 92 is gemcitabine, carboplatin, or paclitaxel.
  • 94 provided is a combination product comprising a first pharmaceutical composition comprising a therapeuticaly effete amount of Compound 1 or a pharmaceuticaly acceptable salt thereof, and a second pharmaceutical composition comprising a therapeuticaly effete amount of an additional therapeutic agent.
  • the additional therapeutic agent is a chemotherapeutic agent.
  • 96 provided is the combination product of embodiments 94, wherein the additional therapeutic agent is a cel cycle checkpoint inhibitor. 97.
  • the additional therapeutic agent is an immune checkpoint inhibitor.
  • the additional therapeutic agent is a MAT2A inhibitor.
  • 99 provided is the combination product of embodiment 95, wherein the chemotherapeutic agent is an alkylating agent.
  • 100 provided is the combination product of embodiment 95, wherein the chemotherapeutic agent is a microtubule inhibitor. Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT 101.
  • the combination product of embodiment 95, wherein the chemotherapeutic agent is an antimetabolite. 102.
  • chemotherapeutic agent is gemcitabine, paclitaxel, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, or satraplatin.
  • the cel cycle checkpoint inhibitor is Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, or adavosertib.
  • embodiment 104 provided is the combination product of embodiment 97, wherein the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • embodiment 105 provided is the combination product of embodiment 94, wherein the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, satraplatin, nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD01
  • 106 provided is the combination product of embodiment 105, wherein the additional therapeutic agent is gemcitabine, carboplatin, or paclitaxel. 107. In embodiment 107, provided is the combination product of embodiment 98, wherein the MAT2A inhibitor is compound 8. 108. In embodiment 108, provided is a PARG inhibitor for use in treating cancer, wherein the PARG inhibitor is to be administered simultaneously or sequentialy with an additional therapeutic agent. 109. In embodiment 109, the PARG inhibitor of embodiment 108 is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof. 110. In embodiment 110, the PARG inhibitor of embodiment 109 is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof as defined in any one of embodiments 4-22. 111.
  • the PARG inhibitor of embodiment 108 or 109 is Compound 11, or a pharmaceuticaly acceptable salt thereof. Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT 112.
  • the PARG inhibitor of embodiment 108 or 109 is Compound 1, or a pharmaceuticaly acceptable salt thereof.
  • the additional therapeutic agent of any one of embodiments 108 to 112 is an additional therapeutic agent described herein.
  • the additional therapeutic agent of any one of embodiments 108 to 112 is a chemotherapeutic agent, a cel cycle checkpoint inhibitor, or an immune checkpoint inhibitor. 115.
  • the PARG inhibitor for use of any one of embodiments 108 to 112, wherein the additional therapeutic agent is a chemotherapeutic agent.
  • the additional therapeutic agent is a cel cycle checkpoint inhibitor.
  • the PARG inhibitor for use of any one of embodiments 108 to 112, wherein the additional therapeutic agent is an immune checkpoint inhibitor.
  • the PARG inhibitor for use of any one of embodiments 108 to 112, wherein the additional therapeutic agent is a MAT2A inhibitor.
  • the PARG inhibitor for use of embodiment 115 wherein the chemotherapeutic agent is an alkylating agent.
  • the PARG inhibitor for use of embodiment 115 wherein the chemotherapeutic agent is a microtubule inhibitor.
  • the PARG inhibitor for use of embodiment 115 wherein the chemotherapeutic agent is an antimetabolite. 122.
  • the PARG inhibitor for use of embodiment 115, wherein the chemotherapeutic agent is gemcitabine, paclitaxel, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, or satraplatin.
  • the chemotherapeutic agent is gemcitabine, paclitaxel, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, or satraplatin.
  • the PARG inhibitor for use of embodiment 116, wherein the cel cycle checkpoint inhibitor is Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, or adavosertib.
  • the cel cycle checkpoint inhibitor is Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, or adavosertib.
  • the PARG inhibitor for use of embodiment 117, wherein the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the PARG inhibitor for use of embodiment 114, wherein the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, satraplatin, nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156,
  • the PARG inhibitor for use of embodiment 125 wherein the additional therapeutic agent is gemcitabine, carboplatin, or paclitaxel.
  • the additional therapeutic agent of embodiment 114 is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, satraplatin, nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the additional therapeutic agent of embodiment 128 is gemcitabine, carboplatin, or paclitaxel. 130.
  • a PARG inhibitor for use in treating cancer wherein the PARG inhibitor is to be administered simultaneously or sequentialy with an additional therapeutic agent; wherein the PARG inhibitor is Compound 1 or a pharmaceuticaly acceptable salt thereof.
  • the PARG inhibitor for use of embodiment 130 wherein the additional therapeutic agent is a chemotherapeutic agent.
  • the PARG inhibitor for use of embodiment 130, wherein the additional therapeutic agent is a cel cycle checkpoint inhibitor. Mintz Docket No.052326-573001WO IDY Ref.
  • No.2023-029-D-PCT 133 provided is the PARG inhibitor for use of embodiment 130, wherein the additional therapeutic agent is an immune checkpoint inhibitor. 134. In embodiment 134, provided is the PARG inhibitor for use of embodiment 130, wherein the additional therapeutic agent is a MAT2A inhibitor. 135. In embodiment 135, provided is the PARG inhibitor for use of embodiment 131, wherein the chemotherapeutic agent is an alkylating agent. 136. In embodiment 136, provided is the PARG inhibitor for use of embodiment 131, wherein the chemotherapeutic agent is a microtubule inhibitor. 137. In embodiment 137, provided is the PARG inhibitor for use of embodiment 131, wherein the chemotherapeutic agent is an antimetabolite.
  • embodiment 138 provided is the PARG inhibitor for use of embodiment 131, wherein the chemotherapeutic agent is gemcitabine, paclitaxel, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, or satraplatin.
  • the chemotherapeutic agent is gemcitabine, paclitaxel, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, or satraplatin.
  • the PARG inhibitor for use of embodiment 132, wherein the cel cycle checkpoint inhibitor is Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, or adavosertib. 140.
  • the PARG inhibitor for use of embodiment 133, wherein the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab. 141.
  • the PARG inhibitor for use of embodiment 130, wherein the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, satraplatin, nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156, ce
  • the PARG inhibitor for use of embodiment 141 wherein the additional therapeutic agent is gemcitabine, carboplatin, or paclitaxel.
  • the PARG inhibitor for use of embodiment 134 wherein the MAT2A inhibitor is compound 8. Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT 144.
  • HRD homologous recombination deficient
  • any one of embodiments 108 to 144 wherein the cancer is characterized by a reduction or absence of BRCA1 gene expression, an absence or mutation of BRCA1, or a reduced function of BRCA1 proteins.
  • 146 provided is the use of any one of embodiments 108 to 145, wherein 9the cancer is characterized by a reduction or absence of BRCA2 gene expression, an absence or mutation of BRCA2 genes, or a reduced function of BRCA2 proteins.
  • 147 provided is the use of any one of embodiments 108 to 146, wherein the cancer is ER positive.
  • 148 provided is the use of any one of embodiments 108 to 147, wherein the cancer is PR positive.
  • 149 In embodiment 149, provided is the use of any one of embodiments 108 to 148, wherein the cancer is HER2 negative. 150. In embodiment 150, provided is the use of any one of embodiments 108 to 149, wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-smal cel lung cancer (NSCLC), and prostate cancer. 151. In embodiment 151, provided is the use of any one of embodiments 108 to 150, wherein the cancer is breast cancer or ovarian cancer. 152. In embodiment 152, provided is a use of a PARG inhibitor in the manufacture of a medicament for treating cancer, wherein the PARG inhibitor is to be administered simultaneously or sequentialy with an additional therapeutic agent. 153.
  • the PARG inhibitor of embodiment 152 is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof. 154.
  • the PARG inhibitor of embodiment 153 is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof as defined in any one of embodiments 4-22.
  • the PARG inhibitor of embodiment 152 or 153 is Compound 11, or a pharmaceuticaly acceptable salt thereof. Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT 156.
  • the PARG inhibitor of embodiment 152 or 153 is Compound 1, or a pharmaceuticaly acceptable salt thereof. 157.
  • the additional therapeutic agent of any one of embodiments 152 to 156 is an additional therapeutic agent described herein. 158.
  • the additional therapeutic agent of any one of embodiments 152 to 156 is a chemotherapeutic agent, a cel cycle checkpoint inhibitor, or an immune checkpoint inhibitor.
  • 159 provided is the use of any one of embodiments 152 to 156, wherein the additional therapeutic agent is a chemotherapeutic agent.
  • 160 provided is the use of any one of embodiments 152 to 156, wherein the additional therapeutic agent is a cel cycle checkpoint inhibitor. 161.
  • the additional therapeutic agent is an immune checkpoint inhibitor. 162.
  • any one of embodiments 152 to 156, wherein the additional therapeutic agent is a MAT2A inhibitor. 163.
  • the chemotherapeutic agent is an alkylating agent. 164.
  • the chemotherapeutic agent is a microtubule inhibitor. 165.
  • the use of embodiment 159, wherein the chemotherapeutic agent is an antimetabolite. 166.
  • embodiment 166 provided is the use of embodiment 159, wherein the chemotherapeutic agent is gemcitabine, paclitaxel, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, or satraplatin. 167.
  • the cel cycle checkpoint inhibitor is Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, or adavosertib. 168.
  • embodiment 161 wherein the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • embodiment 169 provided is the use of embodiment 158, wherein the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, satraplatin, nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156
  • embodiment 170 provided is the use of embodiment 169, wherein the additional therapeutic agent is gemcitabine, carboplatin, or paclitaxel. 171. In embodiment 171, provided is the use of embodiment 162, wherein the MAT2A inhibitor is compound 8. 172.
  • the additional therapeutic agent of embodiment 158 is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, satraplatin, nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the additional therapeutic agent of embodiment 172 is gemcitabine, carboplatin, or paclitaxel.
  • 174 provided is a use of a PARG inhibitor in the manufacture of a medicament for treating cancer, wherein the PARG inhibitor is to be administered simultaneously or sequentialy with an additional therapeutic agent; wherein the PARG inhibitor is Compound 1 or a pharmaceuticaly acceptable salt thereof. 175.
  • the additional therapeutic agent is a chemotherapeutic agent.
  • 176 provided is the use of embodiments 174, wherein the additional therapeutic agent is a cel cycle checkpoint inhibitor. 177.
  • embodiment 177 provided is the use of embodiments 174, wherein the additional therapeutic agent is an immune checkpoint inhibitor. 178. In embodiment 178, provided is the use of embodiments 174, wherein the additional therapeutic agent is a MAT2A inhibitor. Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT 179. In embodiment 179, provided is the use of embodiment 175, wherein the chemotherapeutic agent is an alkylating agent. 180. In embodiment 180, provided is the use of embodiment 175, wherein the chemotherapeutic agent is a microtubule inhibitor. 181. In embodiment 181, provided is the use of embodiment 175, wherein the chemotherapeutic agent is an antimetabolite. 182.
  • embodiment 182 provided is the use of embodiment 175, wherein the chemotherapeutic agent is gemcitabine, paclitaxel, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, or satraplatin.
  • the cel cycle checkpoint inhibitor is Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, or adavosertib. 184.
  • embodiment 177 wherein the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • embodiment 185 provided is the use of embodiment 174, wherein the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156, ceralasertib, camonsertib, VE821, AZD6672, SRA737, rabusertib, prexasertib, SCH900776, adavosertib, cladribine, clofarabine, cytarabine, floxuridine, mechlorethamine, perfosamide, carboplatin, cisplatin, satraplatin, nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, atezolizumab, avelumab, atezolizumab, or durvalumab.
  • the additional therapeutic agent is gemcitabine, paclitaxel, Ku60019, AZD0156
  • embodiment 186 provided is the use of embodiment 185, wherein the additional therapeutic agent is gemcitabine, carboplatin, or paclitaxel. 187. In embodiment 187, provided is the use of embodiment 178, wherein the MAT2A inhibitor is compound 8. 188. In embodiment 188, provided is the use of any one of embodiments 152 to 187, wherein the cancer is a homologous recombination deficient (HRD) cancer. 189. In embodiment 189, provided is the use of any one of embodiments 152 to 188, wherein the cancer is characterized by a reduction or absence of BRCA1 gene expression, an absence or mutation of BRCA1 genes, or a reduced function of BRCA1 proteins.
  • HRD homologous recombination deficient
  • Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT 190 provided is the use of any one of embodiments 152 to 189, wherein the cancer is characterized by a reduction or absence of BRCA2 gene expression, an absence or mutation of BRCA2 genes, or a reduced function of BRCA2 proteins. 191. In embodiment 191, provided is the use of any one of embodiments 152 to 190, wherein the cancer is ER positive. 192. In embodiment 192, provided is the use of any one of embodiments 152 to 191, wherein the cancer is PR positive. 193. In embodiment 193, provided is the use of any one of embodiments 152 to 192, wherein the cancer is HER2 negative. 194.
  • any one of embodiments 152 to 193, wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-smal cel lung cancer (NSCLC), and prostate cancer.
  • NSCLC non-smal cel lung cancer
  • 195 provided is the use of any one of embodiments 152 to 194, wherein the cancer is breast cancer or ovarian cancer.
  • 196 provided is the method of any one of embodiments 1 to 49, wherein the cancer is characterized by microsatelite instability-high (MSI-H).
  • MSI-H microsatelite instability-high
  • 197. provided is the method of any one of embodiments 1 to 49, wherein the cancer is characterized by microsatelite stable (MSS). 198.
  • any one of embodiments 108 to 195, wherein the cancer is characterized by microsatelite instability-high (MSI-H).
  • MSI-H microsatelite instability-high
  • 199 provided is the use of any one of embodiments 108 to 195, wherein the cancer is characterized by microsatelite stable (MSS).
  • 200 provided is a method of treating cancer in a subject in need thereof, the method comprising (a) obtaining a biological sample from the subject; (b) determining if the biological sample is i) a homologous recombination deficient (HRD) cancer; i) an ER positive cancer; ii) a PR positive cancer; Mintz Docket No.052326-573001WO IDY Ref.
  • HRD homologous recombination deficient
  • No.2023-029-D-PCT iv) a HER2 negative cancer; v) a cancer characterized by a reduction or absence of BRCA1 and/or BRCA2 gene expression, the absence or mutation of BRCA1 and/or BRCA2 genes, or reduced function of BRCA1 and/or BRCA2 proteins, or combination thereof; vi) microsatelite instability-high (MSI-H), microsatelite instability-low (MSI-L), or microsatelite stable (MSS); or vi) any combination of i) to vi); and (c) administering to the subject a therapeuticaly effete amount of a Poly ADP-ribose glycohydrolase (PARG) inhibitor and therapeuticaly effete amount of an additional therapeutic agent if the biological sample is i) a homologous recombination deficient (HRD) cancer; i) an ER positive cancer; ii) a PR positive cancer; iv) a HER2 negative cancer; v) a cancer characterized by a reduction or
  • a pharmaceutical composition comprising a PARG inhibitor, or a pharmaceuticaly acceptable salt thereof, an additional therapeutic agent, or a pharmaceuticaly acceptable salt thereof, and at least one pharmaceuticaly acceptable carrier.
  • a pharmaceutical composition comprising a therapeuticaly effete amount of a PARG inhibitor and a second pharmaceutical composition comprising a therapeuticaly effete amount of an additional therapeutic agent is provided.
  • a combination product comprising a first pharmaceutical composition comprising a therapeuticaly effete amount of a PARG Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT inhibitor and a second pharmaceutical composition comprising a therapeuticaly effete amount of an additional therapeutic agent.
  • the PARG inhibitor is a compound of Formula (I): I) or a variables are defined supra.
  • the PARG inhibitor is Compound 1 or a pharmaceuticaly acceptable salt thereof.
  • the additional therapeutic agent is gemcitabine.
  • the additional therapeutic agent is paclitaxel.
  • the additional therapeutic agent is Ku60019.
  • the additional therapeutic agent is AZD0156.
  • the additional therapeutic agent is ceralasertib. In an embodiment, the additional therapeutic agent is camonsertib. In an embodiment, the additional therapeutic agent is VE821. In an embodiment, the additional therapeutic agent is AZD6672. In an embodiment, the additional therapeutic agent is SRA737. In an embodiment, the additional therapeutic agent is rabusertib. In an embodiment, the additional therapeutic agent is prexasertib. In an embodiment, the additional therapeutic agent is SCH900776. In an embodiment, the additional therapeutic agent is adavosertib. In an embodiment, the additional therapeutic agent is cladribine. In an embodiment, the additional therapeutic agent is clofarabine. In an embodiment, the additional therapeutic agent is cytarabine.
  • the additional therapeutic agent is floxuridine. In an embodiment, the additional therapeutic agent is raloxifene. In an embodiment, the additional therapeutic agent is mechlorethamine. In an embodiment, the additional therapeutic agent is perfosamide. In an embodiment, the additional therapeutic agent is carboplatin. In an embodiment, the additional therapeutic agent is cisplatin. In an embodiment, the additional therapeutic agent is satraplatin. In an embodiment, the additional therapeutic agent is nivolumab. In an embodiment, the additional therapeutic agent is pembrolizumab. In an embodiment, the additional therapeutic agent is cemiplimab. In an embodiment, the additional therapeutic agent is dostarlimab. In an embodiment, the additional therapeutic agent is zimberelimab.
  • the additional therapeutic agent is retifanlimab. In an embodiment, the additional therapeutic agent is atezolizumab. In an embodiment, the Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT additional therapeutic agent is avelumab. In an embodiment, the additional therapeutic agent is atezolizumab. In an embodiment, the additional therapeutic agent is durvalumab. In yet another aspect, provided herein is a combination product comprising a first pharmaceutical composition comprising a therapeuticaly effete amount of Compound 1 or a pharmaceuticaly acceptable salt thereof; and a second pharmaceutical composition comprising a therapeuticaly effete amount of an additional therapeutic agent described herein.
  • a pharmaceutical composition comprising a therapeuticaly effete amount of Compound 1 or a pharmaceuticaly acceptable salt thereof; an additional therapeutic agent described herein; and a pharmaceuticaly acceptable carrier.
  • the compounds of Formula (I), or a pharmaceuticaly acceptable salt thereof, provided herein may be in the form of compositions suitable for administration to a subject.
  • such compositions are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof and one or more pharmaceuticaly acceptable carriers.
  • the pharmaceutical compositions may be used in the methods disclosed herein; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic methods and uses described herein.
  • the pharmaceutical compositions can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein. Furthermore, the pharmaceutical compositions may be used in combination with other therapeuticaly active agents or compounds as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.
  • Al the compounds and pharmaceutical compositions provided herein can be used in al the methods provided herein.
  • the compounds and pharmaceutical compositions provided herein can be used in al the methods for treatment and/or prevention of al diseases or disorders provided herein.
  • Administration / Dosage / Formulations In another aspect, provided herein is a pharmaceutical composition or pharmaceutical combination comprising the compounds disclosed herein, together with a pharmaceuticaly acceptable carrier.
  • PARG inhibitor, or a pharmaceuticaly acceptable salt thereof, and additional therapeutic agent are in the same formulation.
  • PARG inhibitor and additional therapeutic Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT agent are in separate formulations.
  • the formulations are for simultaneous or sequential administration. Administration of the combination includes administration of the combination in a single formulation or unit dosage form, administration of the individual agents of the combination concurently but separately, or administration of the individual agents of the combination sequentialy by any suitable route. The dosage of the individual agents of the combination may require more frequent administration of one of the agent(s) as compared to the other agent(s) in the combination.
  • packaged pharmaceutical products may contain one or more dosage forms that contain the combination of agents, and one or more dosage forms that contain one of the combination of agents, but not the other agent(s) of the combination.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effete to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level wil depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors wel, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skil in the art may readily determine and prescribe the effete amount of the pharmaceutical composition required.
  • the physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed Compound 1t levels lower than that required in order to achieve the desired therapeutic effect and gradualy increase the dosage until the desired effect is achieved.
  • Dosage unit form refers to physicaly discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the disclosed Compound 1nd the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a Mintz Docket No.052326-573001WO IDY Ref.
  • No.2023-029-D-PCT disclosed compound for the treatment of pain, a depressive disorder, or drug addiction in a patient.
  • the compounds provided herein are formulated using one or more pharmaceuticaly acceptable excipients or carriers.
  • the pharmaceutical compositions provided herein comprise a therapeuticaly effete amount of a disclosed Compound 1 and a pharmaceuticaly acceptable carrier. The optimum ratios, individual and combined dosages, and concentrations of the drug compounds that yield eficacy without toxicity are based on the kinetics of the active ingredients’ availability to target sites. Routes of administration of any of the compositions discussed herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
  • the compounds may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginaly), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • the preferred route of administration is oral.
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pils, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pelets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions are not limited to the particular formulations and compositions that are described herein.
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceuticaly excipients that are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose, calcium carbonate, sodium carbonate, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as cornstarch or alginic acid, binding agents such as starch, gelatin, or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc, antioxidants such as ascorbic acid and sodium bisulfate, preservatives such as, benzyl alcohol, methyl parabens, ethyl or n- propyl, p-hydroxybenzoate, emulsifying agents, suspending agents, dispersing agents, Mintz Docket No.052326-573001WO IDY Ref.
  • an inert diluent such as lactose, calcium carbonate, sodium carbonate, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as cornstarch or alginic acid
  • binding agents such
  • No.2023-029-D-PCT solvents filers, bulking agents, detergents, bufers, vehicles, and/or adjuvants. Additionaly such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceuticaly elegant and palatable preparations.
  • a suitable vehicle may be physiological saline solution or citrate bufered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration.
  • Neutral bufered saline or saline mixed with serum albumin are further exemplary vehicles.
  • Those skiled in the art wil readily recognize a variety of bufers that can be used in the pharmaceutical compositions and dosage forms contemplated herein.
  • Typical bufers include, but are not limited to, pharmaceuticaly acceptable weak acids, weak bases, or mixtures thereof.
  • the bufer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof.
  • Acceptable bufering agents include, for example, a Tris bufer, N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-Morpholino)ethanesulfonic acid (MES), 2-(N-Morpholino)ethanesulfonic acid sodium salt, 3-(N-Morpholino)propanesulfonic acid (MOPS), and N- tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion.
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionaly containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used. In one embodiment, it may be administered via injection.
  • Kits In an aspect, the present disclosure provides a kit for treating cancer comprising a PARG inhibitor, or a pharmaceuticaly acceptable salt thereof, and an additional therapeutic agent or a pharmaceuticaly acceptable salt thereof.
  • the kit comprises a pharmaceutical product comprising a pharmaceutical composition comprising PARG inhibitor, or a pharmaceuticaly acceptable salt thereof, and a pharmaceuticaly acceptable carrier or diluent; and a pharmaceutical composition comprising an additional therapeutic agent or a pharmaceuticaly acceptable salt thereof, and a pharmaceuticaly acceptable carrier or diluent.
  • a pharmaceutical composition comprising a PARG inhibitor, or a pharmaceuticaly acceptable salt thereof; an additional therapeutic agent, or a pharmaceuticaly acceptable salt thereof; and a pharmaceuticaly acceptable carrier or diluent.
  • pharmaceutical kits are provided.
  • the kit includes a sealed container approved for the storage of pharmaceutical compositions, the container containing one of the above-described pharmaceutical compositions.
  • the sealed container minimizes the contact of air with the ingredients, e.g. an airless botle.
  • the sealed container is a sealed tube.
  • An instruction for the use of the composition and the information about the composition are to be included in the kit.
  • the compounds of the combination can be dosed on the same schedule, whether by administering a single formulation or unit dosage form containing al of the compounds of the combination, or by administering separate formulations or unit dosage forms of the compounds of the combination. However, some of the compounds used in the combination may be administered more frequently than once per day, or with diferent frequencies that other compounds in the combination.
  • the kit contains a formulation or unit dosage form containing al of the compounds in the combination of compounds, and an additional formulation or unit dosage form that includes one of the compounds in the combination of agents, with no additional active compound, in a container, with instructions for administering the dosage forms on a fixed schedule.
  • the kits provided herein include prescribing information, for example, to a patient or health care provider, or as a label in a packaged pharmaceutical formulation. Prescribing information may include for example eficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical formulation.
  • the combination of compounds of the disclosure can be administered alone, as mixtures, or with additional active agents.
  • a kit provided herein can be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing).
  • a kit can contain a label or packaging insert including identifying information for the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredient(s), including mechanism(s) of action, pharmacokinetics and pharmacodynamics, adverse effectss, contraindications, etc.).
  • Each component of the kit can be enclosed within an individual container, and al of the various containers can be within a single package.
  • Labels or inserts can include manufacturer information such as lot numbers and expiration dates.
  • No.2023-029-D-PCT insert can be, e.g., integrated into the physical structure housing the components, contained separately within the physical structure, or afixed to a component of the kit (e.g., an ampule, syringe or vial).
  • kit e.g., an ampule, syringe or vial.
  • Example 1 Preparation of Compound 1
  • Step 1 Preparation of 2,6-difluoro-4-iodobenzaldehyde Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT
  • THF 500 mL
  • LDA 80 mL, 625.0 mmol
  • DMF 48.3 mL, 625mmol
  • reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2 x 300 mL), the combined organic phases were washed with brine solution (200 mL), dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to get crude product as an oil.
  • the crude material was purified by column chromatography using silica gel (100-200) and eluted with 20% EtOAc/Hexane as a gradient. The product was eluted with a gradient of 30% EtOAc/Hexane.
  • Step 2 Preparation of 4-fluoro-6-iodo-1H-indazole
  • 2,6-difluoro-4-iodobenzaldehyde (Intermediate 2)
  • 1,4 dioxane 110 mL
  • hydrazine hydrate 18.6 mL, 373.1 mmol
  • the reaction mixture was concentrated under reduced pressure and ice cold water (100 mL) was added. The mixture was stired for 30 min during which time solid was precipitated out. The mixture was filtered.
  • Step 3 Preparation of 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazol-1-yl)-1,3,4- thiadiazole Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT
  • cesium carbonate 18.6 g, 57.24 mmol
  • 2-bromo-5- (difluoromethyl)-1,3,4-thiadiazole (Intermediate 4) (3.8 g, 18.1 mmol, Enamine Stock Building Blocks, CAS 1340313-49-6, catalogue #EN300-108825).
  • Step 4 Preparation of S-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H- indazol-6-yl) benzothioate
  • 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazol-1-yl)-1,3,4- thiadiazole (Intermediate 5) (100 mg, 0.25 mmol) in toluene (1 mL) degassed for 5 min, was added CuI (5mg, 0.025 mmol), 1,10-phenanthroline (phen) (11 mg, 0.05 mmol), and potassium thiobenzoate (67 mg, 0.378mmol) at RT.
  • Step 5 Preparation of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide indazol-6-yl) benzothioate (Intermediate 6) (500 mg, 1.23 mmol) in acetonitrile (10 mL) at 0 oC were added a solution of BnMe3NCl (682 mg, 3.69 mmol), and TCCA (trichloroisocyanuricacid) (370 mg 1.59 mmol) in acetonitrile (40 mL). The reaction mixture was stired for 20 min.
  • the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x30 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulphate, filtered and the filterate was concentrated under reduced pressure to obtain crude product.
  • the crude product was purified by column chromatography using silica gel (100-200) and eluted with 5 to 50% EtOAc/hexane as a gradient. The product was eluted at 20% EtOAc/hexane.
  • Step 6 Preparation of tert-butyl (2S,6S)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6- (N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1- carboxylate
  • 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (Intermediate 7) (80 mg, 0.19 mmol) in DMSO (dimethyl sulfoxide) (2 mL) were added tert-butyl (2S,6S)-2,6-dimethylpiperazine-1- carboxylate (85 mg, 0.39 mmol, BLD Pharmatech, CAS 574007-66-2, catalogue #
  • Step 7 Preparation of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-((3S,5S)-3,5- dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (Compound 1) Mintz Docket No.052326-573001WO IDY Ref.
  • Example 2 Efficacy study assessing combination effects between Compound 1 and Gemcitabine in the HR deficient breast cancer line HCC1428 (ER+/PR+/HER2- BRCA2mut) The combination effect between Compound 1 and Gemcitabine was assessed using a cel line derived xenograft (CDX) model of the breast cancer line HCC1428 harboring a confirmed pathogenic BRCA2 mutation.
  • CDX cel line derived xenograft
  • HCC1428 cels were expanded in RPMI 1640 with 10% fetal bovine serum and implanted into immunocompromised mice.
  • supplemental estradiol benzoate injections (40 ⁇ g/20 ⁇ l/mouse) were administered subcutaneously twice a Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT week, starting one week prior to cel implantation, and continuing through to the end of treatment. Animals were randomized into diferent treatment arms once a mean tumor volume of approximately 180 mm3 was achieved, at which point eight mice were assigned to each of seven treatment groups.
  • Vehicle 1 administered PO/QD, was the vehicle for Compound 1 and was 0.5% methylcelluloseose (400 cps) + 0.5%Tween 80 in distiled water, and Vehicle 2, administered IP/QW, was the vehicle for gemcitabine and was USP saline.
  • Compound 1 was administered at 30 mg/kg and 100 mg/kg, leading to a TGI of 63% and 103% respectively, and gemcitabine at 100 mg/kg had a TGI of 67%.
  • the combination arms at 30 mg/kg and 100 mg/kg Compound 1 resulted in a more robust and sustained response with a TGI of 81% and 106% respectively.
  • Example 3 Efficacy study assessing combination effects between Compound 1 and Carboplatin in the HR deficient breast cancer line HCC1428 (ER+/PR+/HER2- BRCA2mut) The combination effect between Compound 1 and Carboplatin was assessed using a cel line derived xenograft (CDX) model of the breast cancer line HCC1428 harboring a confirmed pathogenic BRCA2 mutation.
  • CDX cel line derived xenograft
  • HCC1428 cels were expanded in RPMI 1640 with 10% fetal bovine serum and implanted into immunocompromised mice.
  • supplemental estradiol benzoate injections (40 ⁇ g/20 ⁇ l/mouse) were administered subcutaneously twice a week, starting one week prior to cel implantation and continuing through to the end of treatment. Animals were randomized into diferent treatment arms once a mean tumor volume of approximately 180 mm3 was achieved. The study consisted of seven treatment arms containing eight mice per group with a duration of 35 days on treatment. Vehicle 1, administered PO/QD, was the vehicle for Compound 1 and was 0.5% methylcelluloseose (400 Mintz Docket No.052326-573001WO IDY Ref.
  • Example 4 Efficacy study assessing combination effects between Compound 1 and Paclitaxel in the HR deficient breast cancer line HCC1428 (ER+/PR+/HER2- BRCA2mut) The combination effect between Compound 1 and paclitaxel was assessed using a cel line derived xenograft (CDX) model of the breast cancer line HCC1428 harboring a confirmed pathogenic BRCA2 mutation.
  • CDX cel line derived xenograft
  • HCC1428 cels were expanded in RPMI 1640 with 10% fetal bovine serum and implanted into immunocompromised mice.
  • supplemental estradiol benzoate injections (40 ⁇ g/20 ⁇ l/mouse) were administered subcutaneously twice a week, starting one week prior to cel implantation and continuing through to the end of treatment. Animals were randomized into diferent treatment arms once a mean tumor volume of approximately 180 mm3 was achieved. The study consisted of seven treatment arms containing eight mice per group with a duration of 35 days on treatment. Vehicle 1, administered PO/QD, was the vehicle for Compound 1 and was 0.5% methylcelluloseose (400 cps) + 0.5%Tween 80 in distiled water, and Vehicle 2, administered IV/QW, was the vehicle for paclitaxel and was USP saline.
  • Compound 1 was administered at 30 mg/kg and 100 mg/kg, leading to a TGI of 63% and 103% respectively, and paclitaxel at 20 mg/kg had a TGI of 100%.
  • the combination arms at 30 mg/kg and 100 mg/kg of Compound 1 resulted in a more robust and sustained response with a TGI of 105% and 110% respectively.
  • No.2023-029-D-PCT between single agent and combination groups were observed with both the 30 mg/kg and 100 mg/kg doses of Compound 1, with the strongest anti-tumor activity achieved with the 100 mg/kg dose which in combination, led to a p value of ⁇ 0.0001 in comparison with monotherapy for both Compound 1 and paclitaxel.
  • the results are ploted in FIG.3A and FIG.3B. These results highlight the robust anticancer eficacy of Compound 1 as a monotherapy and a deeper more durable response in combination with paclitaxel.
  • Example 5 Efficacy study assessing combination effectss between Compound 1 and the anti-mouse PD-1 inhibitor RMP1-14 in the syngeneic mouse line H22.
  • the combination effect between Compound 1 and the anti-mouse PD-1 inhibitor RMP1-14 was assessed in the H22 syngeneic mouse model-consisting of murine hepatocellular carcinoma H22 cels injected into fuly immunocompetent BALB/C mice.
  • H22 cels were expanded in RPMI 1640 with 10% fetal bovine serum and implanted into immunocompetent mice. Animals were randomized into diferent treatment arms once a mean tumor volume of approximately 98mm3 was achieved. The study consisted of five treatment arms containing ten mice per group with a duration of 28 days on treatment. TGI was calculated on Day 10 when the vehicle was terminated as the alowable tumor burden was reached.
  • the vehicle arm for this study was 0.5% methylcelluloseose (400 cps) +0.5%Tween 80 (vehicle for Compound 1).
  • Compound 1 was administered at 100 mg/kg, leading to a TGI of 44%, and the PD-1 inhibitor RMP1-14 administered at 0.25 mg/kg had a TGI of 75%.
  • the combination of both agents led to a TGI of 78% with 6 out of 10 animals showing robust regressions by Day 28 with the single agent PD-1 inhibitor only showing robust regression in 2 out of 10 animals.
  • the results are ploted in FIG.4. These results highlight the robust anticancer eficacy of Compound 1 in combination with PD-1 inhibition.
  • Example 6 Combination of PARG Inhibitor and Platinum-based Chemotherapy agents Demonstrate Synergistic Growth Inhibition in In Vitro Breast and Ovarian Models.
  • Materials and Methods A panel of 14 breast and ovarian cancer cel lines was used to assess the combinatory effect of a PARG inhibitor (Compound 1) and platinum-based chemotherapy agents such as Carboplatin, Cisplatin and Satraplatin.
  • a PARG inhibitor Compound 1
  • platinum-based chemotherapy agents such as Carboplatin, Cisplatin and Satraplatin.
  • To determine the optimal concentration range of each compound in each cel line for the combination screen cels were seeded at a density of 500 cels/wel in a 384-wel plate. After 24 hours, cels were Mintz Docket No.052326-573001WO IDY Ref.
  • No.2023-029-D-PCT treated with a 9-point titration of each compound as a single agent and incubated at 37°C with 5% CO2 for 6 days to identify concentrations of compounds that wil be tested in combination.
  • cels were seeded at 500 cels/wel in a 384-wel plate. After 24 hours, cels were co-treated with a 5-point titration of each compound in an optimized 6x6 dose matrix and incubated at 37°C with 5% CO2 for 6 days. At the end of 6 days, cel viability was measured using CyQuantTM Direct according to the manufacturer's protocol and data was acquired using an EnVision plate reader (Revvity) for cel number quantification.
  • a plate of untreated cels was harvested at the time of compound addition (T0 or time zero) for cel number quantification using CyQuantTM Direct. Each data point was run in technical triplicate. The percent of growth inhibition is calculated as: If T ⁇ V0 : 100*(1-(T-V0)/V0) If : ) where T is the signal measure treated control measure, and V is the vehicle c 0 ontrol is used to generate dose-response curves and GI50 calculations for single drug activity and drug combination synergy using the Chalice Analyzer software (Horizon).100% and > 100% growth inhibition represented cytostasis and cytotoxicity, respectively. Synergistic growth inhibition was assessed using the Loewe additivity model.
  • Synergy Score log fX log fY ⁇ max(0,Idata)(Idata – ILoewe)
  • the fractional inhibition for each component agent and combination point in the matrix is calculated relative to the median of al untreated/vehicle-treated control wels.
  • a Synergy Score of ⁇ 3 was considered synergistic, given that it corresponded with high growth inhibition and ⁇ 20% excess over Loewe additivity model at multiple dose points. Results
  • the combination of Compound 1 and 3 diferent platinum agents was tested in a panel of 14 breast and ovarian cancer cel lines. Synergistic growth inhibition was observed with each combination, but to varying degrees across the cel line panel.
  • the combination of Compound 1 with Carboplatin enhanced the growth inhibition observed Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT compared to either single agent and showed synergy (as determined by synergy score of ⁇ 3) in 5/14 breast and ovarian cel lines (FIGs.5A-5N and 6A-6N; Table 1).
  • Enhanced growth inhibition compared to single agent treatment and synergy was also seen in the combination of Compound 1 with Cisplatin in 5/14 breast and ovarian cel lines (FIGs.7A-7N and 8A-8N; Table 1).
  • each cel line for the combination screen cels were seeded at a density of 500 cels/wel in a 384-wel plate. After 24 hours, cels were treated with a 9-point titration of each compound as a single agent and incubated at 37°C with 5% CO2 for 6 days to identify concentrations of compounds that wil be tested in combination. For the combination screen, cels were seeded at 500 cels/wel in a 384-wel plate.
  • cels were co-treated with a 5- point titration of each compound in an optimized 6x6 dose matrix and incubated at 37°C with 5% CO TM 2 for 6 days.
  • cel viability was measured using CyQuant Direct according to the manufacturer's protocol and data was acquired using an EnVision plate reader (Revvity) for cel number quantification.
  • a plate of untreated cels was harvested at the time of compound addition (T0 or time zero) for cel number quantification using CyQuantTM Direct. Each data point was run in technical triplicate.
  • the percent of growth inhibition is calculated as: If T ⁇ V0 : 100*(1-(T-V0)/V0) If : ) where T is the signal vehicle-treated control measure, and V0 is the vehicle growth inhibition is used to generate dose-response curves and GI50 calculations for single drug activity and drug combination synergy using the Chalice Analyzer software (Horizon).100% and > 100% growth inhibition represented cytostasis and cytotoxicity, respectively. Synergistic growth inhibition was assessed using the Loewe additivity model. The observed growth inhibition at each dose was compared to the predicted inhibition based on the additive activity of either drug combined with itself.
  • the combination of Compound 1 with Compound 2 enhanced the growth inhibition observed compared to either single agent and showed synergy (as determined by synergy score of ⁇ 3) in 7/14 breast and ovarian cel lines (FIGs.11A-11N and 12A-12N; Table 2).
  • the combination of Compound 1 with Compound 3 showed enhanced growth inhibition compared to single agents and showed synergy in 6/14 breast and ovarian cel lines (FIGs. 13A-13N and 14A-14N; Table 2).
  • the combination of Compound 1 and Ceralasertib also enhanced the growth inhibition observed with either single agent and showed synergy in 9/14 breast and ovarian cel lines (FIGs.15A-15N and 16A-16N; Table 2).
  • Enhanced growth inhibition compared to single agent treatment and synergy was also seen in the combination of Compound 1 with Camonsertib in 9/14 breast and ovarian cel lines (FIGs.17 and 18; Table 2).
  • Synergy was also seen in combination of Compound 1 with Compound 4 in 8/14 breast and ovarian cel lines (FIGs.19A-19N and 20A-20N; Table 3).
  • the combination of Compound 1 with Compound 5 also showed enhanced growth inhibition over single agents and synergy in 11/14 breast and ovarian cel lines (FIGs.21A-21N and 22A-22N; Table 3).
  • Combination of Compound 1 with Compound 6 showed enhanced growth inhibition and synergy in 7/14 breast and ovarian cel lines (FIGs.23A-23N and 24A-24N; Table 3).
  • the combination of Compound 1 with Rabusertib showed synergy and enhanced growth inhibition over single agents in 11/14 breast and ovarian cel lines (FIGs.25A-25N and 26A- 26N; Table 3).
  • Combination of Compound 1 with Prexasertib showed enhanced growth inhibition and synergy in 8/14 breast and ovarian cel lines (FIGs.27A-27N and 28A-28N; Table 4).
  • Combination of Compound 1 with Compound 7 showed enhanced growth inhibition and synergy in 10/14 breast and ovarian cel lines (FIGs.29A-29N and 30A-30N; Table 4).
  • cels were seeded at a density of 500 cels/wel in a 384-wel plate. After 24 hours, cels were treated with a 9-point titration of each compound as a single agent and incubated at 37°C with 5% CO2 for 6 days to identify concentrations of compounds that wil be tested in combination.
  • cels were seeded at 500 cels/wel in a 384-wel plate. After 24 hours, cels were co-treated with a 5-point titration of each compound in an optimized 6x6 dose matrix and incubated at 37°C with 5% CO2 for 6 days.
  • the percent growth inhibition is used to generate dose-response curves and GI50 calculations for single drug activity and drug combination synergy using the Chalice Analyzer software (Horizon).100% and > 100% growth inhibition represented cytostasis and cytotoxicity, respectively. Synergistic growth inhibition was assessed using the Loewe additivity model. The observed growth inhibition at each dose was compared to the predicted inhibition based on the additive activity of either drug combined with itself. The calculation for Loewe additivity is: Mintz Docket No.052326-573001WO IDY Ref.
  • a Synergy Score of ⁇ 3 was considered synergistic, given that it corresponded with high growth inhibition and ⁇ 20% excess over Loewe additivity model at multiple dose points.
  • Results The combination of Compound 1 and 5 diferent anti metabolite drugs was tested in a panel of 14 breast and ovarian cancer cel lines. Synergistic growth inhibition was observed with each combination, but to varying degrees across the cel line panel. For instance, the combination of Compound 1 with Cladribine enhanced the growth inhibition observed compared to either single agent and showed synergy (as determined by synergy score of ⁇ 3) in 6/14 breast and ovarian cel lines (FIGs.33A-33N and 34A-34N; Table 5).
  • the combination of Compound 1 with Clofarabine showed enhanced growth inhibition compared to single agents and exhibited synergy in 5/14 breast and ovarian cel lines (FIGs.35A-35N and 36A-36N; Table 5).
  • the combination of Compound 1 and Cytarabine also enhanced the growth inhibition observed with either single agent and demonstrated synergy in 9/14 breast and ovarian cel lines (FIGs.37A-37N and 38A-38N; Table 5).
  • Enhanced growth inhibition compared to single agent treatment and synergy was also seen in the combination of Compound 1 with Gemcitabine Hydrochloride in 6/14 breast and ovarian cel lines (FIGs. 39A-39N and 40A-40N; Table 6).
  • cels were co-treated with a 5-point titration of each compound in an optimized 6x6 dose matrix and incubated at 37°C with 5% CO2 for 6 days.
  • cel viability was measured using CyQuantTM Direct according to the manufacturer's protocol and data was acquired using an EnVision plate reader (Revvity) for cel number quantification.
  • a plate of untreated cels was harvested at the time of compound addition (T0 or time zero) for cel number quantification using CyQuantTM Direct. Each data point was run in technical triplicate.
  • the percent of growth inhibition is calculated as: If T ⁇ V0 : 100*(1-(T-V0)/V0) If : ) where T is the signal vehicle-treated control measure, and V0 is the vehicle growth inhibition is used to generate dose-response curves and GI50 calculations for single drug activity and drug combination synergy using the Chalice Analyzer software (Horizon).100% and > 100% growth inhibition represented cytostasis and cytotoxicity, respectively. Synergistic growth inhibition was assessed using the Loewe additivity model. The observed growth inhibition at each dose was compared to the predicted inhibition based on the additive activity of either drug combined with itself.
  • a Synergy Score of ⁇ 3 was considered synergistic, given that it corresponded with high growth inhibition and ⁇ 20% excess over Loewe additivity model at multiple dose points.
  • Results The combination of Compound 1 and 2 diferent alkylating agents was tested in a panel of 14 breast and ovarian cancer cel lines. Synergistic growth inhibition was observed Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT with each combination, but to varying degrees across the cel line panel.
  • the combination of Compound 1 with Mechlorethamine Hydrochloride enhanced the growth inhibition observed compared to either single agent and showed synergy (as determined by synergy score of ⁇ 3) in 8/14 breast and ovarian cel lines (FIGs.43A-43N and 44A-44N; Table 7).
  • Enhanced growth inhibition compared to single agent treatment and synergy was also seen in the combination of Compound 1 with Perfosamide in 6/14 breast and ovarian cel lines (FIGs.45A-45N and 46A-46N; Table 7).
  • Table 7 Synergy scores for the combination of Compound 1 and either Mechlorethamine Hydrochloride or Perfosamide in 14 breast and ovarian cel lines.
  • the study consisted of four treatment arms containing ten mice per group with a Mintz Docket No.052326-573001WO IDY Ref. No.2023-029-D-PCT duration of 60 days on treatment. TGI was calculated on Day 21 when the vehicle was terminated as the alowable tumor burden was reached.
  • the vehicle arm in this study was 0.5% methylcelluloseose (400 cps) +0.5%Tween 80 (vehicle for Compound 1 and 8).
  • Compound 1 was administered at 100mg/kg and Compound 8 as 10mg/kg, leading to a TGI of 80% and 85% respectively as monotherapy.
  • Example 11 Combination of PARG Inhibitor and MAT2A inhibitor Demonstrate Synergistic Growth Inhibition in In Vitro Gastric Model.
  • a gastric MTAP-nul cancer cel line (SNU-16) was used to assess the combinatory effect of a PARG inhibitor (Compound 1) and MAT2A inhibitor (Compound 8).
  • a PARG inhibitor Compound 1
  • MAT2A inhibitor Compound 8
  • To determine the optimal concentration range of each compound in the cel line for the combination screen cels were seeded at either 250 or 500 cels/wel in a 96-wel plate. After 24 hours, cels were treated with a 9-point titration of each compound as a single agent and incubated at 37°C with 5% CO2 for 13 days to identify concentrations of compounds that wil be tested in combination. Media and compounds were replenished after 6-days of treatment.
  • cels were seeded at the optimal seeding density (250 cels/wel) in a 96-wel plate. After 24 hours, the SNU16 cel line was treated with 8-point titration of compound 8 and 5-point titration of compound 1 in an optimized 9x6 dose matrix. Treated cels were incubated at 37°C with 5% CO2 for 13 days, and media and compounds were replenished after 7-days of treatment. Cel viability was measured using CelTiter-Glo 2.0 (Promega) according to the manufacture’s protocol and data was acquired using the Envision Multimode plate reader (PerkinElmer). Each data point was run in quadruplicate.

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Abstract

La présente invention concerne une association d'un inhibiteur de PARG et d'un agent thérapeutique supplémentaire. L'invention concerne également des méthodes d'utilisation de telles associations pour traiter des maladies ou des troubles, par exemple, le cancer.
PCT/US2024/047598 2023-09-20 2024-09-20 Polythérapie avec un inhibiteur de parg Pending WO2025064750A1 (fr)

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