USP1 Program

TNG348 is 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.

• In vivo preclinical studies of USP1 inhibition have shown single agent efficacy in BRCA1 and BRCA2-mutant cell-line and patient derived xenografts, including those that are intrinsically resistant to PARP inhibition. These preclinical data further demonstrate that TNG348 is synergistic with PARP inhibition across a panel of human ovarian and breast cancer cell lines, including both PARP inhibitor resistant and sensitive lines.
• We are planning future clinical trials with TNG348 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.