USP1 (ubiquitin-specific protease 1) is a de-ubiquitinating enzyme that is essential for the survival and proliferation of BRCA1/2-mutant and other HRD+ (homologous recombination deficient) cancer cells, thus making USP1 inhibition synthetic lethal with BRCA1/2 mutations. Normal cells have multiple mechanisms to repair damaged DNA and prevent cell death, while BRCA 1/2 mutant cells rely on translesion synthesis and base excision repair. Inhibiting USP1 impairs translesion synthesis and thereby DNA replication, leading to cell death in BRCA1/2-mutant cancer cells. Combining USP1 and PARP inhibitors, which also impair DNA damage repair in BRCA1/2-mutant cells, demonstrate the potential for even greater benefit.
HRD+ cancers, including BRCA1 and BRCA2-mutations, represent up to 50% of ovarian, 25% of breast, 10% of prostate and 5% of pancreatic cancers. In vivo preclinical studies for TNG348 have shown single agent efficacy and combination benefit with PARP inhibitors in BRCA1/2-mutant and other HRD+ cell-line and patient derived xenografts, including those that are intrinsically resistant to PARP inhibition.