Discovery of Dual PARP/GPX4 Inhibitors for the Treatment of Triple-Negative Breast Cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors have achieved clinical success in BRCA-mutated triple-negative breast cancer (TNBC), while their clinical utility remains limited in BRCA wild-type (WT) tumors. Co-targeting of PARP and other oncogenic signaling pathways represents an effective strategy to broaden the therapeutic applicability of PARP inhibitors in TNBC patients. Herein, we identified dual PARP/GPX4 inhibitors via a structure-based hybridization strategy and explored the dual-target antitumor effect in blocking the progression of TNBC. We found that compound 12 exhibited potent biochemical inhibitory activities against both PARP and GPX4. In both BRCA-mutated and BRCA-WT TNBC cells, compound 12 exerts superior antitumor efficacy by exerting a dual impact on DNA damage and ferroptosis induction. In both HCC1937 and MDA-MB-231 xenografts, compound 12 exhibited potent in vivo antitumor activity with efficacy superior to both single agents and combined treatment. Our findings highlight the potential of dual PARP/GPX4 inhibitors in overcoming the limitations of PARP inhibitors in anti-TNBC.