Development of a Highly Selective Ferroptosis Inducer Targeting GPX4 with 2-Ethynylthiazole-4-carboxamide as Electrophilic Warhead.

A highly selective ferroptosis inducer with drug-like properties can significantly advance the research on inducing ferroptosis for anticancer treatment. We previously reported a highly active GPX4 inhibitor , but its activity and stability need further improvement. In this work, a novel GPX4 inhibitor with more potent cytotoxicity (IC = 0.0003 μM against HT1080) and ferroptosis selectivity (selectivity index = 24933) was gained via further electrophilic warhead screening and structure-based optimization. The cellular thermal shift assay (CETSA) indicated that could stabilize GPX4 with a value of 6.2 °C. Furthermore, showed strong binding affinity against GPX4 ( = 20.4 nM). More importantly, has more favorable pharmacokinetic properties than , which endowed with potential in antitumor research and as a tool drug for further study of ferroptosis. Associated with these, treatment significantly inhibited tumor growth in the xenograft tumor mouse model without detectable toxicity.