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WO2025087941A1 - Inhibiteurs de parg en combinaison avec des inhibiteurs de parp et leurs utilisations - Google Patents

Inhibiteurs de parg en combinaison avec des inhibiteurs de parp et leurs utilisations Download PDF

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WO2025087941A1
WO2025087941A1 PCT/EP2024/079889 EP2024079889W WO2025087941A1 WO 2025087941 A1 WO2025087941 A1 WO 2025087941A1 EP 2024079889 W EP2024079889 W EP 2024079889W WO 2025087941 A1 WO2025087941 A1 WO 2025087941A1
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inhibitor
parg
parp
inhibitors
mice
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Athanassios HALAZONETIS
Giacomo Rossetti
Michail Petropoulos
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Universite de Geneve
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

  • the present invention pertains generally to the field of agents useful in the treatment of cancer, in particular cancers associated with Homologous recombination (HR) repair deficiency and useful compositions for the treatment of those.
  • HR Homologous recombination
  • Cancer is defined as an unrestrained growth of tissue. In terms of human health, cancer is one of the leading causes of death worldwide and, therefore, is a major health issue (Jemal et al, 2011, CA Cancer J Clin., 61(2): 69-90)' .
  • HR deficiency is most prevalent in ovarian, breast, prostate, and pancreatic cancers. HR deficiency can make tumors sensitive to poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitors. PARP inhibition is therefore synthetic lethal with HR deficiency (Bryant et al., 2005, Nature, 434(7035) :913-917) and PARP inhibitors are part of the standard- of-care for HR-deficient cancers.
  • ADP adenosine diphosphate
  • PARP inhibitors are part of the standard- of-care for HR-deficient cancers.
  • Novel PARP inhibitors and new modalities for therapy are also being developed, including combining PARP inhibitors with other therapeutic modalities (for example: Das et al., 2024, Eur. J. Med. Chem., 274: 116535; McKay et al., 2024, Cancer Treat. Rev., 126: 102726; Papageorgiou et al., 2024, Immunother., PMID: 39268937; Bardia et al., 2024, Clin. Cancer Res., 30: 2917-2924; Bourlon et al, 2024, Ther. Adv. Med.
  • talazoparib, olaparib, niraparib, rucaparib, pamiparib and senaparib inhibit PARP1 and PARP2, whereas saruparib (AZD5305), AZD9574 and HRS-1167 are selective inhibitors of PARP1 (Frederick et al. , 2024, Int. J. Mol. Sci., 25: 9032; Menear et al., 2008, J. Med. Chem., 51: 6581-6591; Thomas et al., 2007, Mol. Cancer Ther., 6: 945-956; Canan- Koch et al., 2002, J. Med.
  • PARP inhibitors limits the ability to combine these agents with other anti-cancer therapies.
  • combining PARP inhibitors with ATR or WEE1 inhibitors leads to increased sensitivity of cancer cell lines in vitro, but in clinical trials these combinations have led to severe myelosuppression and anemia that precluded their further clinical development (Lallo et al., 2018, Clin. Cancer Res., 24:5153-5164; Mahdi et al., 2021, JCO Precis. Oncol., 5: PO.20.00439; Yap et al., 2022, JCO Precis. OncoL, 6: e2100456; Bhamidipati et al., 2023, Br. J. Cancer, 129: 904-916).
  • PARP inhibitors Efforts have also been made to combine PARP inhibitors with PARG inhibitors for the treatment of cancer. PARPs promote PAR chain formation, whereas PARG hydrolyses PAR chains (Slade, 2020, Genes Dev., 34: 360-394). Therefore, a reasonable expectation would be that PARG inhibitors suppress the efficacy of PARP inhibitors against HR-deficient cancer cells. In other words, the expectation would be that the combination of PARP and PARG inhibitors would not be better or even worse than administering PARP inhibitor alone. Indeed, the PARG inhibitor PDDX-04 suppresses the olaparib-induced lethality of HR-deficient cells SUM149T and DLD I -BRCA2' ' (Gogola at el., 2018, supra).
  • PARP inhibitors have very different effects than reducing PARP gene expression, as documented by multiple studies (for example: Murai et al, 2012, Cancer Res., 72: 5588-5599; Petropoulos et al., 2024, supra).
  • reducing the expression of PARG may not be equivalent to administering PARG inhibitors.
  • the authors did not examine the effect of olaparib alone on tumor volume, which is needed to determine whether suppressing PARG gene expression affects the efficacy of PARP inhibitors.
  • the authors did not determine the number of red blood cells or the body weight of the treated mice (Chand et al., 2018, supra).
  • talazoparib the most potent clinically-approved PARP inhibitor
  • PARP Poly(ADP-ribosyl)ation
  • PARylation is an abundant protein post-translational modification involved in a variety of essential cellular functions, including transcription, cell cycle progression and DNA repair. PARylation has been characterized mainly in the context of DNA damage, where PAR polymerases (PARPs) play a major role.
  • PARP1 is the main producer of PAR chains.
  • PARP1 In response to DNA single-strand breaks, PARP1 goes to sites of damage and catalyzes the assembly of branched PAR chains on itself and its target proteins, thereby facilitating the recruitment of repair factors (Chaudhuri & Nussenzweig, 2017, Nat Rev Mol Cell Biol., 18(10):610-621).
  • PARG poly(ADP -ribose) glycohydrolase
  • PARP1 hyperactivation causes excessive and cytotoxic PAR accumulation (Andrabi et al, 2006, Proc Natl Acad Sci USA, 103(48): 18308-1831 S').
  • PARG-deficient mice show excessive PAR chain accumulation resulting in early embryonic lethality (Koh et al, 2004, Proc Natl Acad Sci USA, 101(51): 17699-17704). Therefore, while PARP inhibitors can suppress PAR chain formation, inhibition of PARG with small molecules leads to PAR chain accumulation in intact cells (James et al, 2016, ACS Chem BioL, ll(ll):3179-3190; Abed et al., 2023, Cancer Res. 2023. 83 (7 Supplement): 6093). This PAR chain accumulation is actually blocked when PARG and PARP inhibitors are co-administered (Pillay N. et al., 2019, supra .
  • the invention is based on the unexpected finding that the combined use of a PARG inhibitor with a PARP inhibitor is beneficial to the treatment of cancers and that the effect of a PARG inhibitor on the anticancer effect of a PARP inhibitor in vitro depends on the potency of the PARP inhibitor and on whether the treated cancer cells are Homologous recombination (HR)- deficient or HR-proficient.
  • a PARG inhibitor e.g. talazoparib
  • potent PARP inhibitors such as talazoparib and saruparib (defined here as having ECso values for inducing lethality of HR-deficient cancer cells in vitro of less than 20 nM, preferably less than 10 nM, and even more preferably less than 5 nM), was not compromised by PARG inhibitors administered at concentrations of about 10-300 nM (effective concentrations of PARG inhibitors can be determined by assays monitoring PAR chain levels, as described in Example 2).
  • the anticancer activity of the less potent PARP inhibitors such as rucaparib, olaparib and niraparib (defined here as having ECso values greater than 20 nM and preferably greater than 50 nM against HR-deficient cancer cells)
  • the anticancer activity of PARP inhibitors against HR-proficient cells was compromised by PARG inhibitors, irrespective of the potency of the PARP inhibitor used.
  • the present invention is based on unexpected combinations of PARP and PARG inhibitors that do not compromise the anticancer effect of the PARP inhibitors against HR-deficient cancer cells and yet reduce the severity of the anemia that is associated with cancer treatment that employs PARP inhibitors.
  • Fig. 1 represents the effect of a combination of the invention in mice as described in Example 3 on the number of red blood cells (M/pl) (A) and the hematocrit (% of red cells in the blood) (B), determined one day after the last treatment compared to control.
  • Fig. 2 plots the tumor volume (mm 3 ), measured on the indicated days after start of the treatment, in mice carrying xenografts of DLD1-BRCA2 -knockout cells, as described in Example 4.
  • In the PARPi group two mice died on day 12, two mice died on day 17 and the last mouse was euthanized on day 19. All other mice were living at the end of the experiment.
  • Fig. 3 plots the body weight (A) and the body weight change (%), relative to the body weight at the start of treatment (B) measured on the indicated days after the start of the treatment, in mice carrying xenografts of DLD1-BRCA2 -knockout cells, as described in Example 4.
  • the PARPi group two mice died on day 12, two mice died on day 17 and the last mouse was euthanized on day 19. All other mice were living at the end of the experiment.
  • Figures 1-3 PARPi: PARP inhibitor talazoparib (0.25 mg/kg); PARGi: PARGi of Formula (1) (25 mg/kg).
  • Fig. 4 represents the effect of a combination of the invention in mice as described in Example 3 on the number of red blood cells (M/pl) (A) and the hematocrit (% of red cells in the blood) (B), determined one day after the last treatment compared to control.
  • M/pl red blood cells
  • B hematocrit
  • the mice received the compounds once daily 4 days ON, 2 days OFF, 4 days ON. Blood was collected one day after the last treatment. Statistical analysis was performed with unpaired t test.
  • Fig. 5 plots dose-response survival curves and calculated ECso values for the PARP inhibitors talazoparib (A), saruparib (B), niraparib (C), olaparib (D) and rucaparib (E) on their own or combined with selected concentrations of PARGi of Formula (2) in a cellular viability assay performed with DLD1 BRCA2 ’ ’ cells as described in Example 5.
  • Fig. 6 plots dose-response survival curves and calculated ECso values for the PARP inhibitors talazoparib (A) and niraparib (B) on their own or combined with selected concentrations of PARGi of Formula (2) in a cellular viability assay performed with BRCA2 -mutated PEO1 cells as described in Example 5.
  • Fig. 7 shows an assay, as described in Example 2, for determining whether a specific compound is a PARG inhibitor.
  • DLD1 BRCA2 ⁇ / ⁇ cells were either untreated or treated with a putative PARG inhibitor (PARGi) alone or, optionally, in combination with the PARP inhibitor talazoparib (Talaz) at the indicated compound concentrations.
  • the putative PARG inhibitor in this experiment is the compound of Formula (3).
  • the cells were treated with the PARG and PARP inhibitors for 24 hours.
  • H2O2 hydrogen peroxide
  • Formation of PAR chains was assayed by immunoblotting with an antibody that recognizes PAR chains. Immunoblotting for GAPDH served as a loading control.
  • Molecular weight (M.W.) markers are shown in the first lane of each gel.
  • Fig. 8 plots dose-response survival curves and calculated EC50 values for induction of lethality of MDA-MB-157 (A), HCC-1569 (B) and U2OS (C) cells by the PARG inhibitor (PARGi) of Formula (3) alone for all cell lines and in combination with PARP inhibitors for the sensitive cell lines, as described in Example 2.
  • the MDA-MB-157 and HCC-1569 cells are very sensitive to the PARG inhibitor alone, but are resistant to the combination of PARG and PARP inhibitors, indicating that the lethality by the PARG inhibitor alone is due to inhibition of PARG and not due to an off-target effect.
  • Fig. 9 represents the effect of a combination of the invention in mice as described in Example
  • the PARP inhibitor (PARPi) was talazoparib (Talaz) and its dose was 0.25 mg/kg daily.
  • the PARG inhibitor (PARGi) was the compound of Formula (3) and its dose ranged from 5-40 mg/kg daily, as indicated. In the PARPi group, two mice died on day 10 and they are not included in the analysis. No other mice died. Each dot in the graph represents one mouse.
  • Fig. 10 represents the effect of a combination of the invention in mice as described in Example 3 on body weight gain-loss, determined one day after the end of treatment.
  • Body weight gainloss was determined relative to body weight one day before the start of treatment.
  • the mice received compounds orally once daily 4 days ON, 2 days OFF, 4 days ON.
  • the PARP inhibitor was saruparib and its dose was 0.1 mg/kg daily.
  • the PARG inhibitor (PARGi) was the compound of Formula (3) and its dose was 20 mg/kg daily.
  • Statistical significance was examined using an unpaired t test. Each symbol in the graph represents one mouse.
  • Fig. 11 represents the effect of a combination of the invention in rats as described in Example 3 on the number of red blood cells (RBC) (10 6 /pl) (A), the hematocrit (HCT) (% of red cells by volume in the blood) (B), and the number of white blood cells (WBC) (10 3 /pl) (C) determined one day after the last treatment, as compared to the vehicle control.
  • the rats received the compounds once daily 4 days ON, 2 days OFF, 4 days ON. Statistical significance was examined using a one-way ANOVA test.
  • the PARP inhibitor used was talazoparib and the daily dose for the first 4 days was 0.25 mg/kg and for the remainder of the study it was 0.5 mg/kg.
  • the PARG inhibitor used was the compound of Formula (3) and the daily dose was 10
  • Fig. 12 plots the tumor volume (mm 3 ), measured on the indicated days after start of the treatment (A) and the body weight change (%), relative to the body weight at the start of treatment (B), in mice carrying xenografts of DLD1-BRCA2 -knockout cells, as described in Example 4.
  • the mice received the compounds once daily on a weekly regimen as follows: 3 days ON, 4 days OFF.
  • the PARPi was talazoparib.
  • the daily dose of talazoparib was 0.25 mg/kg for days 1-11 of the experiment; no PARPi was administered on day 12 and the daily dose was reduced to 0.1 mg/kg from day 13 until the end of the experiment. These dose reductions were implemented because of observed toxicity, including weight loss.
  • the daily dose of talazoparib was 0.25 mg/kg for days 1-12 and 0.2 mg/kg from day 13 until the end of the experiment.
  • the PARGi was the compound of Formula (2) and its daily dose was 50 mg/kg in the PARGi and in the PARPi + PARGi combination groups.
  • Fig. 13 plots the tumor volume (mm 3 ), measured on the indicated days after start of the treatment (A) and the body weight change (%), relative to the body weight at the start of treatment (B), in mice carrying xenografts of DLD1-BRCA2 -knockout cells, as described in Example 4.
  • the mice received the compounds once daily on a weekly regimen as follows: 3 days ON, 4 days OFF.
  • the PARPi was talazoparib and its daily dose was 0.25 mg/kg throughout the experiment for both the PARPi and PARPi + PARGi groups.
  • the PARGi was the compound of Formula (3) and its daily dose was 20 mg/kg in the PARPi + PARGi combination groups. All mice were living at the end of the experiment.
  • Fig. 14 plots the tumor volume (mm 3 ), measured on the indicated days after start of the treatment (A) and the body weight change (%), relative to the body weight at the start of treatment (B), in mice carrying xenografts of DLD1-BRCA2 -knockout cells, as described in Example 4.
  • the mice received the compounds once daily on a weekly regimen as follows: 3 days ON, 4 days OFF.
  • the PARPi was saruparib and its daily dose was 0.1 mg/kg throughout the experiment for both the PARPi and PARPi + PARGi groups.
  • the PARGi was the compound of Formula (2) and its daily dose was 50 mg/kg in the PARGi and in the PARPi + PARGi combination groups. All mice were living at the end of the experiment.
  • Fig. 15 plots dose-response survival curves and calculated ECso values for the PARP inhibitor talazoparib alone or in combination with the PARG inhibitor (PARGi) of Formula (3) (Form- 3) in a cellular viability assay performed with ///riN2-mutant HCC-1569 cells, as described in Example 5.
  • Fig. 16 plots dose-response survival curves and calculated ECso values for the PARP inhibitors talazoparib (A) or niraparib (B) alone or in combination with the PARG inhibitor (PARGi) of Formula (2) (Form-2) in a cellular viability assay performed with HR-proficient DLD1 BRCA2 +/+ cells, as described in Example 5.
  • Fig. 16 plots dose-response survival curves and calculated ECso values for the PARP inhibitors talazoparib (A) or niraparib (B) alone or in combination with the PARG inhibitor (PARGi) of Formula (2) (Form-2) in a cellular viability assay performed with HR-proficient DLD1 BRCA2 +/+ cells, as described in Example 5.
  • PARG inhibitor refers to an agent able to reduce, block or inhibit the activity of poly(ADP-ribose) glycohydrolase (PARG).
  • PARG inhibitors are 4-substituted indole and indazole sulfonamido derivatives from WO 2021/055744 of the following structure as defined in this document, the content of which is incorporated herein by reference.
  • a particular example of a PARG inhibitor is the compound of Formula (1) as shown below, which is described in WO 2021/055744, as example 24:
  • a PARG inhibitor is the specific stereoisomer thereof of Formula (2):
  • a particular example of a PARG inhibitor is the compound of Formula (3) as shown below, which is described in WO 2023/057389, as example 284, as having the highest PARG inhibitory activity among the examples described in Table 2 of this document.
  • PARG inhibitors are described in WO 2023/224998, WO 2024/002284, WO 2023/208092, WO 2023/154913, WO 2022/138812 and WO 2024/023330 and inhibit PARG in cells according to the methods detailed in Example 2.
  • PARP inhibitor refers to an agent able to reduce, block or inhibit the activity of poly(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP1) and, optionally, other members of the PARP family, such as PARP2.
  • PARP1 poly(adenosine diphosphate (ADP)-ribose) polymerase 1
  • PARP2 poly(adenosine diphosphate)-ribose) polymerase 1
  • PARP inhibitors according to the invention inhibit PARylation in cells exposed to DNA damaging agents with IC50 values ranging between 0.1 and 20 nanomolar (Petropoulos et al., 2024, Nature, 628: 433-441) and typically induce lethality of HR-deficient cancer cells in vitro with EC50 values similar to the IC50 values mentioned above (Petropoulos et al., 2024, supra).
  • Assays to monitor inhibition of PARylation in cells have been described in the literature (for example: Petropoulos etal., 2024, supra).
  • Potent PARP inhibitors such as talazoparib (CAS n° 1207456-01-6 ) and saruparib (AZD5305, CAS n° 2589531-76-8), inhibit PARylation in cells with IC50 values ⁇ 10 nM.
  • Further examples of PARP inhibitors according to the invention include HRS- 1167 (M9466), pamiparib (BGB-290, CAS n° 1446261-44-4) and AZD9574 (CAS n° 2756333-39-6).
  • the expression “cancer disorder characterized by HR- deficiency” refers to cancers presenting HR impairment of which is associated with inherited susceptibility to hereditary tumors.
  • HR deficiency (HRD) is most prevalent in ovarian, breast, prostate, and pancreatic cancers. In a pan-cancer cohort reported by Nguyen et al., 2020, Nat. Commun., 11:5584.
  • a PARG inhibitor for use in the treatment of a cancer disorder characterized by HR-deficiency, wherein said treatment comprises the use of a PARP inhibitor, wherein said PARP inhibitor is characterized by ECso values for inducing lethality of HR-deficient cancer cells in vitro of less than 20 nM, preferably less than 10 nM, and even more preferably less than 5 nM.
  • a method of treating a patient suffering from a cancer disorder characterized by HR-deficiency comprising the administration of a PARG inhibitor in combination with a PARP inhibitor, wherein said PARP inhibitor is characterized by ECso values for inducing lethality of HR-deficient cancer cells in vitro of less than 20 nM, preferably less than 10 nM, and even more preferably less than 5 nM.
  • a pharmaceutical composition comprising at least one PARG inhibitor in combination with at least one PARP inhibitor and at least one pharmaceutically acceptable carrier, diluent or excipient thereof, wherein said PARP inhibitor is characterized by ECso values for inducing lethality of HR-deficient cancer cells in vitro of less than 20 nM, preferably less than 10 nM, and even more preferably less than 5 nM.
  • a pharmaceutical composition according to the invention for use as a medicament.
  • composition according to the invention for use in the treatment of a cancer characterized by HR-deficiency.
  • the said cancer is an ovarian, breast, prostate, or pancreatic cancer.
  • said PARG inhibitor is to be administered in combination with a PARP inhibitor concomitantly with a PARP inhibitor.
  • said PARG inhibitor and PARP inhibitor are administered in the same or different compositions and in the same or different routes of administration.
  • said PARG inhibitor is as described in WO 2021/055744.
  • said PARG inhibitor is of Formula (1).
  • said PARG inhibitor is as described in WO 2023/183850.
  • said PARG inhibitor is of Formula (2).
  • said PARG inhibitor is as described in WO 2023/057389.
  • said PARG inhibitor is of Formula (3).
  • said PARP inhibitor is selected from talazoparib, saruparib, HRS- 1167 (M9466), pamiparib and AZD9574.
  • the PARP inhibitor is talazoparib.
  • the PARP inhibitor is saruparib.
  • the PARP inhibitor is HRS- 1167 (M9466).
  • the PARP inhibitor is pamiparib.
  • the PARP inhibitor is AZD9574.
  • the use of the combination according to the invention results in a reduced toxicity of the PARP inhibitor.
  • a PARP inhibitor for use in a combination is a PARP inhibitor able to induce lethality in HR-deficient cell lines (e.g. in cell survival assays of homologous recombination deficient DLD1 or PEO1 cells as described herein) with a ECso value ⁇ 20 nM, preferably ⁇ 10-nM and even more preferably ⁇ 5 nM.
  • the PARG inhibitor is to be administered at a dose that inhibits PARG activity in cells, typically said dose ranging between 10-1000 mg daily.
  • PARG inhibitors, PARP inhibitors and compositions thereof of this invention may be administered in any manner including via oral, intramuscular or intravenous routes or combinations thereof.
  • the PARG inhibitor, PARP inhibitor and compositions thereof are administered orally.
  • the pharmaceutical compositions of the invention are oral formulations.
  • Example 1 Synthesis of a PARG inhibitor of formula (1) or of Formula (2) or Formula (3)
  • a PARG inhibitor according to the invention can belong to a family of 4-substituted indole and indazole sulfonamido derivatives.
  • a PARG inhibitor can be of Formula (1) and synthesized from an intermediate Int-A4 as exemplified below under Scheme 1:
  • a PARG inhibitor according to the invention can also belong to a family of piperazine substituted indazole derivatives.
  • a PARG inhibitor can be of Formula (2) and synthesized from an intermediate Int-B5 as exemplified below under Scheme 2:
  • a PARG inhibitor according to the invention can also belong to a family of imidazo[l,5-a] pyridine derivatives.
  • a PARG inhibitor can be of Formula (3) and synthesized from an intermediate Int-C12 as exemplified below under Scheme 3:
  • reaction mixture was stirred for 10 min., then 2,2-difluoroacetohydrazide (13.7 g, 124.5 mmol, 1.5 equiv.) was added at rt and stirred reaction mixture at the same temperature 2h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched by the addition of ice-cold water, extracted 10% MeOH in DCM, the combined organic layers were collected washed with aqueous NaHCCL, brine, dried over Na2SO4, filtered, filtrate was concentrated to give crude compound.
  • reaction mixture was degassed with nitrogen for 20 min then added Xantphos (1.65 g, 2.8 mmol, 0.1 equiv.) and Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (1.48 g, 1.4 mmol, 0.05 equiv.) at room temperature and stirred the reaction mixture at 80 °C for 16h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated on rotavapor, the crude compound was purified by 100-200 silica gel column purification eluted by 10% ethyl acetate in pet ether to obtain Int-C7 (10 g, 88.8%) as a pale-yellow solid.
  • reaction mixture quench with water and extracted with DCM (twice) and combined organic layer and wash with brine, dried over anhydrous ISfeSCU, filtered and filtrate was concentrated under reduced pressure to obtain Int- C9 (12 g, crude) as a semi solid.
  • the combination of a PARP inhibitor (PARPi) with a PARG inhibitor (PARGi) was also examined in rats (Fig. 11).
  • the rats received the compounds once daily 4 days ON, 2 days OFF, 4 days ON.
  • Statistical significance was examined using a one-way ANOVA test.
  • the PARP inhibitor used was talazoparib and the daily dose for the first 4 days was 0.25 mg/kg and for the remaining of the study was 0.5 mg/kg (same doses applied in the single arm and in the combination).
  • the PARG inhibitor used was the compound of Formula (3) and the daily dose was 10 mg/kg (same dose applied in the single arm and in the combination).
  • the number of red blood cells (RBC) (10 6 /pl) (A), the hematocrit (HCT) (% of red cells by volume in the blood) (B), and the number of white blood cells (WBC) (10 6 /pl) (C) were determined one day after the last treatment.
  • the combination of the invention rescued the anemia induced by the PARPi, but not the neutropenia.
  • Example 4 In vivo effect of the administration of PARG inhibitor together with PARP inhibitor
  • CDX cell-line derived xenograft
  • the PARP inhibitor (PARPi) talazoparib was administered as monotherapy or in combination with a PARG inhibitor (PARGi) of formula (1) to mice carrying xenografts of DLD1-BRCA2- knockout cells (Figs 2 and 3).
  • the daily dose of talazoparib was 0.25 mg/kg; the daily dose of the PARG inhibitor was 25 mg/kg.
  • the mice were not treated on Days 17-18 (week 3) and on Day 23 (week 4), because two mice of the talazoparib group died on Day 12, two more mice of the talazoparib group died on Day 17 and the last mouse of the talazoparib group was sick and had to be euthanized on Day 19.
  • a second xenograft experiment in mice adjusted the dose of the PARP inhibitor (PARPi) talazoparib during the experiment to prevent deaths of mice treated with this agent.
  • the mice carried xenografts of DLD1-BRCA2 -knockout cells and tumor volume (mm 3 ) (Fig. 12A) and body weight changes relative to the body weight at the start of the experiment (Fig. 12B) were plotted over time.
  • the PARPi was talazoparib.
  • the daily dose of talazoparib was 0.25 mg/kg for days 1-11 of the experiment; no PARPi was administered on day 12 and the daily dose was reduced to 0.1 mg/kg from day 13 until the end of the experiment. These dose reductions were implemented because of observed toxicity, including weight loss.
  • the daily dose of talazoparib was 0.25 mg/kg for days 1- 12 and 0.2 mg/kg from day 13 until the end of the experiment.
  • the PARGi was the compound of Formula (2) and its daily dose was 50 mg/kg in the PARGi and in the PARPi + PARGi combination groups. Despite the PARPi dose reductions in the PARPi group, one mouse in this group died on day 24 and another mouse died on day 31. In the vehicle and PARGi groups, the mice were euthanized on day 28 due to the large tumor size. All other mice were living at the end of the experiment (day 44). As seen by the graphs, tumor growth was better controlled in the mice receiving the combination of the invention than in the mice receiving only the PARPi (Fig. 12A). This was attributed to the higher dose of talazoparib used in the mice receiving the combination of the invention.
  • mice receiving only talazoparib In the mice receiving only talazoparib, it was not possible to achieve such a high dose of the PARPi, because of toxicity and animal deaths.
  • the mice treated with talazoparib also lost more weight than all the other groups of mice (Fig. 12B).
  • the “improvement” in weight gain of the mice in the talazoparib group after day 21 is due to the death of the animals that had suffered the greatest weight loss.
  • Tumor volume (mm 3 ), was measured on the indicated days after start of the treatment (Fig. 13A) and the body weight change (%) was measured relative to the body weight at the start of treatment (Fig. 13B).
  • the mice carried xenografts of DLD1-BRCA2 -knockout cells.
  • the PARPi was talazoparib and its daily dose was 0.25 mg/kg throughout the experiment for both the PARPi and PARPi + PARGi groups.
  • the PARGi was the compound of Formula (3) and its daily dose was 20 mg/kg in the PARPi + PARGi combination group. All mice were living at the end of the experiment. In this experiment we were able to maintain the daily dose of talazoparib at 0.25 mg/kg in both the PARPi and the PARPi + PARGi combination groups. As a result, tumor growth was controlled to the same extent in both these groups (Fig. 13A). However, the animals in the PARPi group lost weight, whereas the mice in the combination group did not lose body weight (Fig. 13B).
  • the PARPi was saruparib and its daily dose was 0.1 mg/kg throughout the experiment for both the PARPi and PARPi + PARGi groups.
  • the PARGi was the compound of Formula (2) and its daily dose was 50 mg/kg in the PARGi and in the PARPi + PARGi combination groups. All mice were living at the end of the experiment. Similar to the third xenograft experiment described above, the dose of the PARPi was the same in the PARPi and PARPi + PARGi groups. As a result, tumor growth was controlled to the same extent in both these groups (Fig. 14A) However, the animals in the PARPi group lost weight, whereas the mice in the combination group did not lose body weight (Fig. 14B).
  • Example 5 In vitro effect of the administration of PARG inhibitor together with a PARP inhibitor The effect of a combination of the invention was also assayed in cell survival assays using homologous recombination (HR)-deficient and HR-proficient cell lines.
  • HR homologous recombination
  • DLD1 BRCA2 ⁇ / ⁇ cells were plated in 96-well black plates with clear flat bottom, at a confluency of 2000 cells per well. After 24 hours, the cells were exposed to various concentrations of a PARP inhibitor alone or in combination with selected concentrations of a PARG inhibitor, wherein the PARP inhibitor used was either talazoparib or saruparib (AZD5303) (from the invention) or, as a comparative, niraparib or olaparib or rucaparib (not from the invention) and the PARG inhibitor used was the one of Formula (2). Cells were incubated with the drugs for 120 hours at 37°C in a cell culture incubator. At the end of the treatment, cell survival was assessed using the CellTiter-Glo® (CTG-Promega) assay. ECso values for each PARP inhibitor were calculated from dose-response curves (Fig. 5).
  • the cell survival assays show that the PARG inhibitor did not compromise significantly the lethality induced by the potent PARP inhibitors talazoparib and saruparib (less than 2-fold increases in ECso values) (Fig. 5A, B). However, the PARG inhibitor compromised between 4- fold and 7-fold the lethality induced by the less potent PARP inhibitors niraparib, olaparib and rucaparib (Fig. 5C-E).
  • HCC-1569 cells which are also AC42-mutant.
  • DLD1 BRCA2 ⁇ / ⁇ and PEO1 cells we observed that the lethality induced by the potent PARP inhibitor talazoparib was not compromised by the PARG inhibitor of Formula (3) (Fig. 15).
  • combinations of PARP and PARG inhibitors according to the invention improve the therapeutic window of cancer therapies employing PARP inhibitors.
  • Said improvement of the therapeutic window is achieved because the combinations do not compromise the anticancer effect of the PARP inhibitors against HR-deficient cancer cells, yet reduce the severity of the anemia that is associated with cancer treatment that employs PARP inhibitors.
  • the patients can be treated with higher doses of PARP inhibitors achieving better clinical efficacy or can be treated with the currently clinically approved doses of the PARP inhibitors and experience fewer adverse events, specifically less anemia.

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Abstract

L'invention concerne l'utilisation combinée d'un inhibiteur de PARG et d'un inhibiteur de PARP dans le traitement de cancers caractérisés par une déficience en réparation de recombinaison homologue (HR) et des compositions utiles pour le traitement de ceux-ci.
PCT/EP2024/079889 2023-10-23 2024-10-23 Inhibiteurs de parg en combinaison avec des inhibiteurs de parp et leurs utilisations Pending WO2025087941A1 (fr)

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