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US-20260125377-A1 - PARG INHIBITORY COMPOUND

US20260125377A1US 20260125377 A1US20260125377 A1US 20260125377A1US-20260125377-A1

Abstract

The present invention relates to a compound of formula (I) or pharmaceutically acceptable salt thereof. The present invention further relates to the compound of formula (I) of the present invention for use in therapy. The compound is particularly useful as PARG inhibitor, and can be used in a method of treatment of a proliferative disorder, preferably of cancer.

Inventors

  • Ulrich Luecking
  • Olivier Querolle
  • Andreas Goutopoulos
  • Jin Tian
  • Sotirios Sotiriou
  • Luca Iacovino
  • Alena Freudenmann

Assignees

  • FORX THERAPEUTICS AG

Dates

Publication Date
20260507
Application Date
20231003
Priority Date
20221003

Claims (15)

  1. 1 . A compound of formula (I): or a tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or a prodrug thereof.
  2. 2 . The compound of claim 1 , wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  3. 3 . The compound of claim 2 , in a non-salt form.
  4. 4 . The compound of claim 2 , which is a formate salt of the compound of formula (I).
  5. 5 . A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.
  6. 6 . The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of claim 5 , for use in therapy.
  7. 7 . The compound for use or the pharmaceutical composition for use of claim 6 , for use in a method of treating a disease or disorder in which PARG activity is implicated.
  8. 8 . The compound for use or the pharmaceutical composition for use of claim 7 , for use in a method of treating a proliferative disorder.
  9. 9 . The compound for use or the pharmaceutical composition for use of claim 8 , wherein the proliferative disorder is cancer.
  10. 10 . Use of the compound of claim 1 in the manufacture of a medicament for the inhibition of PARG enzyme activity.
  11. 11 . Use of the compound of claim 1 in the manufacture of a medicament for the treatment of a proliferative condition.
  12. 12 . Use of claim 11 , wherein the proliferative condition is cancer.
  13. 13 . A method of treating a disease or disorder in which PARG activity is implicated in a subject or patient in need thereof, the method comprising administering to said subject/patient a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  14. 14 . A method of treating a proliferative disorder in a subject or patient in need thereof, the method comprising administering to said subject/patient a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  15. 15 . The method of claim 14 , wherein the proliferative disorder is cancer.

Description

FIELD OF THE INVENTION The present invention relates to a compound of formula (I): or pharmaceutically acceptable salt thereof. The present invention further relates to the compound of formula (I) of the present invention for use in therapy. Instant compound is particularly useful as PARG inhibitor and can be used in a method of treatment of a proliferative disorder, preferably of cancer. BACKGROUND OF THE INVENTION Cancer is a leading cause of death worldwide. Although progression-free survival and overall survival of cancer patients has improved over the past two decades, millions of cancer patients still have few therapeutic options and poor survival outcomes (Jemal et al., J. Natl. Cancer Inst. 2017, 109, 1975). DNA replication stress (DRS) is a hallmark of cancer cells and a major source of genomic instability (a) Halazonetis et al., Science 2008, 319, 1352; b) Negrini et al., Nat. Rev. Mol. Cell Biol. 2010, 11, 220). In broad terms, DRS refers to the deregulation of DNA replication and cell cycle progression. DRS can be induced from endogenous or exogenous causes such as oncogene activation and chemotherapeutics, respectively (Zeman and Cimprich, Nat. Cell Biol. 2013, 16, 2). At the level of the replication fork, DRS leads to replication fork stalling, disengagement of the replisome and eventually collapse. Several DNA repair proteins are involved in replication fork stability, protection, and restart under DRS conditions (a) Costantino et al., Science 2014, 343, 88; b) Scully et al., Curr. Opin. Genet. Dev. 2021 71, 154). Poly(ADP)ribosylation (PARylation) is a transient and reversible post-translational modification that occurs at DNA damaged sites and is catalyzed by the poly (ADP-ribose) polymerase (PARP) family of proteins (Cohen and Chang, Nat. Chem. Biol. 2018, 14, 236). PARylation of various DNA repair proteins leads to their activation. Degradation of the poly(ADP) ribose chains is mediated primarily by the poly(ADP-ribose) glycohydrolase (PARG) protein. DNA damage dependent PARylation/dePARylation is a rapid and dynamic process which needs to be well regulated since imbalances between the two processes can lead to DNA damage. Human PARG encodes a 111 kDa protein of 976 amino acids. It contains a N-terminal regulatory domain, a catalytic domain and an ADP-ribose binding macrodomain. Five human PARG transcripts have been identified. Full length PARG is mostly nuclear; the smaller isoforms localize primarily to the cytoplasm. PARG functions primarily as an exo-hydrolase and it releases mainly mono(ADP-ribose) by hydrolyzing the α-O-glycosidic ribose-ribose bond in PAR. PARG can also act as an endo-hydrolase. PARG preferentially degrades long and linear PAR chains whereas its activity with small and branched PAR chains is significantly reduced (O'Sullivan et al., Nat. Commun. 2019, 10, 1182). Although PARG is the dominant cellular PAR degrading enzyme, it cannot act on the terminal protein-ribose bond. Additional hydrolases such as terminal ADP-ribose protein glycohydrolase (TARG1) and ADP-ribosylhydrolase 3 (ARH3) are also known to catalyze PAR-degradation. TARG1 and ARH3 complete the reversal of PARylation by removing protein-bound mono(ADP-ribose) moieties (a) Fontana et al., Elife 2017, doi: 10.7554/eLife.28533; b) Rack et al., Genes Dev. 2020, 34, 263). TARG1 is located in the nucleus and cytoplasm. ARH3 is found primarily in the cytoplasm but it can also be found in the mitochondria and in the nucleus (Rack et al., Genes Dev. 2020, 34, 263). Genomic aberrations targeting tumor suppressor genes or oncogenes, often make cancer cells dependent on specific DNA repair pathways. For instance, it is well known that PARP inhibitors are particularly effective against tumors carrying mutations in the BRCA1 and BRCA2 genes (a) Bryant et al., Nature 2005, 434, 913; b) Farmer et al., Nature 2005, 434, 917). Targeting synthetic lethal interactions like the one between PARP and BRCA is an attractive novel therapeutic approach for cancer treatment. PARG participates in DNA replication and in various DNA repair mechanisms including single-strand break (SSB) repair and replication fork restart. PARG inhibitors have shown synthetic lethal phenotype in cells with high levels of DRS caused by low expression of genes involved in DNA replication and/or replication fork stability (Pillay et al., Cancer Cell. 2019, 35, 519). Moreover, PARG inactivation, depletion or inhibition sensitizes cells to irradiation and to DNA damaging agents such as alkylating agents (e.g. temozolomide and methyl methanesulfonate) (a) Fujihara et al., Curr. Cancer Drug Targets 2009, 9, 953; b) Gogola et al., Cancer Cell 2018, 33, 1078; c) Houl et al., Nat Commun. 2019, 10, 5654). Given the therapeutic potential of PARG inhibitors in cancer treatment, there is an increased need for the development of highly potent and selective PARG inhibitors beyond the ones that have already been described (a) James et al., ACS Chem. Biol. 2016, 11, 317