USP1, one of the best characterized human deubiquitinating enzymes ("DUBs"), plays an important role in the cellular response to DNA Damage.

USP1 regulates DNA repair by deubiquitylating DNA repair proteins, including PCNA-ubiquitin ("PCNA-Ub") pathway for DNA translesion synthesis, as well as FANCD2-ubiquitin ("FANCD2-Ub") and FANCI-ubiquitin ("FANCI-Ub") in Fanconi anemia ("FA") pathways for intra-strand crosslink repair. By reverting PCNA monoubiquitination, USP1 contributes to prevent unscheduled recruitment of TLS polymerases, and thus help maintaining genome stability.

Similarly, Ubiquitylated FANCI-FANCD2 is directed to DNA lesions and functions as a platform to colocalize with specific nucleases and interact with downstream DNA repair proteins, initiating the ICL correction. USP1 deubiquitinates the modified FANCI-FANCD2 complex, thereby reverting the crucial events in the FA pathway, which is crucial for the correct function of the FA pathway in intra strand repair.

Therefore, inhibition of USP1 by small molecule inhibitors such as ISM3091 leads to inhibition of DNA damage repair, which has great potential for the treatment of tumors lacking homologous recombination and DNA repair.

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.

ISM initiated an AI-designed program targeting USP1 and nominated a preclinical candidate for anti-cancer therapies targeting USP1. In vitro data showed potent anti-proliferation activity of the compound in BRCA mutant tumor cells with excellent selectivity. In vivo efficacy studies in CDX and PDX models showed strong anti-tumor activity and robust/durable tumor regression both in monotherapy group and when combined with Olaparib.