hrd+

AZD-9574 is a selective inhibitor of PARP1 at the sites of SSBs. AZD-9574 exhibits anti-cancer activities and can be used in studies about HRD+ breast cancer and advanced solid malignancies.

EXO1-IN-1 (Compound F684) is a potent and selective inhibitor of exonuclease 1 (EXO1) with an IC50 of 15.7 μM. It inhibits DNA end resection, promotes the accumulation of DNA double-strand breaks, and induces S-phase polyadenylation, thereby disrupting DNA repair pathways in homologous recombination-deficient (HRD) cancer cells. This selectivity effectively targets and kills tumor cells with homologous recombination gene defects, such as BRCA1/2 mutations. EXO1-IN-1 holds promise for researching cancers with homologous recombination deficiencies, including BRCA-related tumors.

TNG348 is an allosteric, selective, and reversible inhibitor of USP1, causing dose-dependent accumulation of ubiquitinated substrates in vitro and in vivo. CRISPR screens demonstrate that TNG348 disrupts DNA damage tolerance by interfering with the translesion synthesis pathway via RAD18-dependent ubiquitinated PCNA. Although both TNG348 and PARP inhibitors selectively kill homologous recombination-deficient tumors, they act through distinct mechanisms: PARP1 knockout confers resistance to PARP inhibitors but sensitizes cells to TNG348. Consistent with this mechanistic divergence, combining TNG348 with PARP inhibitors results in synergistic antitumor efficacy, including tumor growth inhibition and regression in multiple HRD mouse xenograft models.