VRTX-531

VRTX-531 is a preclinical, orally bioavailable small-molecule inhibitor of ubiquitin-specific peptidase 1 (USP1), developed as a best-in-class agent for homologous recombination–deficient (HRD) and BRCA1/2-mutant cancers, including triple-negative breast cancer and gynecologic malignancies.[1][2][3][4][5][6][7] It is a potent, selective, allosteric USP1 inhibitor (sub-50 nM biochemical IC50) that disrupts USP1-mediated deubiquitination within the DNA damage response, thereby impairing homologous recombination repair, increasing ubiquitinated PCNA, and inducing synthetic lethality in HRD tumors, with strong single-agent antitumor activity and marked synergy in combination with PARP inhibitors in BRCA-mutant and HRD-positive xenograft models.[1][2][3][4][6][7] VRTX-531 has demonstrated favorable pharmacokinetics, oral exposure, and tolerability in preclinical toxicology studies, supporting its advancement through IND-enabling development as a targeted anticancer therapy.[1][2][4][5][6][7]