• Inhibits the TMEJ activity in cells and induces excessive DSB end resection and RAD51 foci.• Inhibits HDR-deficient (BRCA1- and BRCA2) breast and ovarian tumors in GEMM, xenograft and PDX models.• Enhances the cytotoxic effect of PARPi in HDR-deficient tumor cells, xenograft and PDX models and overcomes acquired PARPi resistance in HR-deficient ovarian cancer PDX model by triggering synthetic lethality.IC50 = 25-50 μM. Here, BRCA2 is linked to neoplasm.