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

• DOI: 10.1021/acs.jmedchem.3c00967
• Publication Date: 2023-07-15T13:34:39Z
• Authors: Tingting Chen; Jiafu Leng; Jun Tan; Yongjun Zhao; Shanshan Xie; Shifang Zhao; Xiangyu Yan; Liqiao Zhu; Jun Luo; Lingyi Kong; Yong Yin
• Keywords: GPX4; Triple-negative breast cancer

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