Discovery of Novel Potent Covalent Glutathione Peroxidase 4 Inhibitors as Highly Selective Ferroptosis Inducers for the Treatment of Triple-Negative Breast Cancer

Abstract

Glutathione peroxidase 4 (GPX4) is a promising target to induce ferroptosis for the treatment of triple-negative breast cancer (TNBC). We designed and synthesized a novel series of covalent GPX4 inhibitors based on RSL3 and ML162 by structural integration and simplification strategies. Among them, compound <b>C18</b> revealed a remarkable inhibitory activity against TNBC cells and significantly inhibited the activity of GPX4 compared to RSL3 and ML162. Moreover, it was identified that <b>C18</b> could notably induce ferroptosis with high selectivity by increasing the accumulation of lipid peroxides (LPOs) in cells. Further study demonstrated that <b>C18</b> covalently bound to the Sec46 of GPX4. Surprisingly, <b>C18</b> exhibited an outstanding potency of tumor growth inhibition in the MDA-MB-231 xenograft model with a TGI value of 81.0%@20 mg/kg without obvious toxicity. Overall, <b>C18</b> could be a promising GPX4 covalent inhibitor to induce ferroptosis for the treatment of TNBC.