USP1 Program

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.
Learn more about our approach.Learn more about our approach.