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 26a, but its activity and stability need further
improvement. In this work, a novel GPX4 inhibitor (R)-9i with more potent cytotoxicity
(IC50 = 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 (R)-9i could stabilize GPX4 with a Tm value of 6.2 °C. Furthermore, (R)-9i showed strong binding affinity
against GPX4 (KD = 20.4 nM). More importantly, (R)-9i has more
favorable pharmacokinetic properties than 26a, which
endowed (R)-9i with potential in antitumor research and as a tool drug for further
study of ferroptosis. Associated with these, (R)-9i treatment significantly
inhibited tumor growth in the xenograft tumor mouse model without
detectable toxicity.