Discovery of a Potent Glutathione Peroxidase 4 Inhibitor as a Selective Ferroptosis Inducer

Abstract

Potent and selective ferroptosis regulators promote an intensive understanding of the regulation and mechanisms underlying ferroptosis, which is highly associated with various diseases. In this study, through a stepwise structure optimization, a potent and selective ferroptosis inducer was developed targeting to inhibit glutathione peroxidase 4 (GPX4), and the structure-activity relationship (SAR) of these compounds was uncovered. Compound <b>26a</b> exhibited outstanding GPX4 inhibitory activity with a percent inhibition up to 71.7% at 1.0 μM compared to 45.9% of RSL-3. At the cellular level, <b>26a</b> could significantly induce lipid peroxide (LPO) increase and effectively induce ferroptosis with satisfactory selectivity (the value of 31.5). The morphological analysis confirmed the ferroptosis induced by <b>26a</b>. Furthermore, <b>26a</b> significantly restrained tumor growth in a mouse 4T1 xenograft model without obvious toxicity.