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.

ISM3091 is a highly selective, orally bioavailable small molecule inhibitor of USP1 identified through lnsilico Medicine's artificial intelligence (Al) platform, with potent activity in BRCA-mutated tumor models.
In September 2023, Insilico and Exelixis announced an exclusive license
agreement with $80 million upfront. In May 2023, the FDA cleared the initial IND for ISM3091 for the treatment of patients with solid tumors.