Dual GPX4/PARP inhibitor YHD-26 exerts potent antitumor activity against triple-negative breast cancer via ferroptosis and DNA damage synergy.

Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, associated with poor prognosis and frequent drug resistance. Ferroptosis refers to an iron-dependent form of non-apoptotic cell death triggered by lipid peroxidation, offering a promising strategy to overcome this resistance. Here, we describe a dual-pharmacophore fusion strategy that hybridizes the electrophilic warhead of a GPX4 inhibitor with the clinical PARP inhibitor niraparib, leading to the design and synthesis of (S)-2-(4-(1-(4-ethynylthiazole-2-carbonyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (YHD-26), a novel ferroptosis inducer. YHD-26 inhibits PARP (IC50 = 92 nM) and binds GPX4 (KD = 23.4 μM). Mechanistically, YHD-26 exerts potent antiproliferative effects, induces ferroptosis, and impairs DNA damage repair, resulting in G2/M arrest in MDA-MB-468 and 4 T1 cells. In a 4 T1 xenograft mouse model, YHD-26 inhibited GPX4 and PARP, validating its in vivo antitumor efficacy and dual-target engagement. Collectively, YHD-26 represents a novel dual GPX4/PARP inhibitor with therapeutic potential for TNBC.