We are developing a potent, selective, and allosteric inhibitor of USP1 (ubiquitin-specific protease 1) that is synthetic lethal with BRCA1 and BRCA2-mutations. BRCA1 or BRCA2 mutations are present in approximately 15% of ovarian cancers, 10% of breast cancers, 5% of prostate cancers, 5% of endometrial and 5% of pancreatic cancers. A subset of lung and ovarian cancer cell lines without BRCA1 or BRCA2 mutations are also sensitive to USP1 inhibition, and work to understand this observation is ongoing.
- Our lead molecules have strong activity in BRCA1/2-mutant patient derived xenografts, including models that are intrinsically resistant to PARP inhibition.
- Preclinical data demonstrate that USP1 inhibition is synergistic with PARP inhibition in multiple PARP inhibitor sensitive and resistant cancer cell lines and xenograft models.
- We plan future clinical trials of a USP1 inhibitor both as a single agent and in combination with PARP inhibitors.
- The anti-cancer activity of USP1 inhibition extends to a panel of BRCA WT lung cancer cell line and xenograft models and we are evaluating potential patient selection biomarkers for this indication.