Ubiquitin-specific protease 1 (USP1), a well-characterized member of the deubiquitinating enzymes family, cleaves ubiquitin from various target proteins. USP-1 expression is dysregulated in many cancers where it acts as an oncogenic driver with roles in various DNA damage repair processes including translesion synthesis and the Fanconi anemia pathway.

Previous data show that USP1 plays a critical role in protecting the replication fork in BRCA1-deficient cells and that its loss results in reduced cell survival and replication fork degradation, suggesting that USP1 inhibitors may be particularly useful in BRCA-deficient tumors. Though PARP inhibitors (PARPi) have shown clinical benefit in BRCA-mutated (BRCAm) populations, some patients either do not respond to therapy or develop resistance.

USP1 inhibitors may have the potential to address this unmet clinical need.

Defects in homologous recombination repair, and replication stability leads to PARP inhibitor sensitivity in BRCA1 deficient tumor cells. USP1 is upregulated in tumors (Breast, ovarian, prostate, and pancreatic carcinomas) with mutations in BRCA1. Also, it exhibits DNA-mediated activation at the replication fork, protecting it, and promoting survival in BRCA1 deficient cells. Inhibition of USP1 leads to replication form destabilization, and decreased viability of BRCA1 deficient cells, exhibiting a synthetically lethal relationship. Hence this inhibition of USP1 may be a useful treatment for a subset of PARP inhibitor resistant BRCA1 deficient tumors with acquired replication fork stabilization. Small molecule inhibitors of USP1 are gaining clinical efficacy either as monotherapy or in combination with PARP inhibitors, due to the rapid emergence of PARP inhibitor resistance in the clinics.

USP1 inhibitors have multiple indications and are a synthetic lethality target in oncology.

Insilico Medicine initiated an AI-designed program targeting USP1 and nominated a preclinical candidate for anti-cancer therapies targeting USP1. In vitro data showed potent anti-survival activity of the compound in BRCA mutant tumor cells with excellent selectivity. In vivo efficacy studies support the future clinical development of this compound as a potential best-in-class USP1 inhibitor not only for PARPi-resistant/responsive HRD-mutant cancers, both, as a single agent as well as in combination with PARPi, but also for subsets of HR-proficient cancers.