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

Glutathione peroxidase 4 (GPX4) is a promising targetto induceferroptosis for the treatment of triple-negative breast cancer (TNBC).We designed and synthesized a novel series of covalent GPX4 inhibitorsbased on RSL3 and ML162 by structural integration and simplificationstrategies. Among them, compound C18 revealed a remarkableinhibitory activity against TNBC cells and significantly inhibitedthe activity of GPX4 compared to RSL3 and ML162. Moreover, it wasidentified that C18 could notably induce ferroptosiswith high selectivity by increasing the accumulation of lipid peroxides(LPOs) in cells. Further study demonstrated that C18 covalentlybound to the Sec46 of GPX4. Surprisingly, C18 exhibitedan outstanding potency of tumor growth inhibition in the MDA-MB-231xenograft model with a TGI value of 81.0%@20 mg/kg without obvioustoxicity. Overall, C18 could be a promising GPX4 covalentinhibitor to induce ferroptosis for the treatment of TNBC.