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 26a 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, 26a 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 26a. Furthermore, 26a significantly restrained tumor growth in a mouse 4T1 xenograft model
without obvious toxicity.