TNG348

TNG348 is a selective, allosteric, and reversible small molecule inhibitor of the deubiquitinating enzyme ubiquitin-specific protease 1 (USP1). It was developed for the treatment of cancers characterized by homologous recombination deficiency (HRD), particularly those with BRCA1/2 mutations. By inhibiting USP1, TNG348 disrupts DNA damage repair pathways—specifically blocking USP1-mediated deubiquitination activity—which leads to replication fork degradation and decreased tumor cell survival. Preclinical studies demonstrated that TNG348 induces synthetic lethality in HRD tumors and has synergistic effects when combined with PARP inhibitors, including overcoming acquired resistance to PARP inhibitors. The drug was evaluated as both a single agent and in combination with olaparib in phase 1/2 clinical trials for BRCA-mutant and HRD+ breast, ovarian, prostate, pancreatic cancers, and other solid tumors. Clinical development was discontinued due to unexpected liver toxicity observed during early trials.