AZD4956

AZD4956 is an investigational, orally bioavailable small molecule inhibitor of Ubiquitin Specific Peptidase 1 (USP1) being developed by AstraZeneca. USP1 is a deubiquitinating enzyme that plays a critical role in the DNA damage response (DDR), specifically within the Fanconi Anemia pathway and the regulation of PCNA-mediated translesion synthesis. By inhibiting USP1, AZD4956 aims to exploit synthetic lethality in tumors with homologous recombination repair (HRR) deficiencies, where the loss of multiple DNA repair pathways leads to genomic instability and cell death. It is currently being evaluated in the Phase I/IIa PARTHENON clinical trial as both a monotherapy and in combination with the PARP1-selective inhibitor saruparib (AZD5305) for the treatment of advanced or metastatic HRR-defective solid tumors, including breast, ovarian, prostate, and pancreatic cancers.