PW2132

PW2132 is an orally bioavailable, potent, and selective small molecule inhibitor of Ubiquitin-Specific Peptidase 1 (USP1), currently under development by Pathway Biopharma for the treatment of advanced solid tumors. USP1 is a deubiquitinating enzyme that plays a critical role in DNA damage repair pathways, particularly the Fanconi Anemia (FA) pathway and the regulation of Translesion Synthesis (TLS) through the deubiquitination of PCNA. By inhibiting USP1, PW2132 promotes the accumulation of ubiquitinated PCNA and FANCD2/FANC1, leading to replication stress, DNA double-strand breaks, and apoptosis. This mechanism exhibits synthetic lethality in tumors with Homologous Recombination Deficiency (HRD), such as those harboring BRCA1/2 mutations, and has the potential to overcome resistance to PARP inhibitors.