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

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 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, 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 . Furthermore, significantly restrained tumor growth in a mouse 4T1 xenograft model without obvious toxicity.