Design, synthesis, and biological evaluation of ML162-based glutathione peroxidase 4 (GPX4) degraders with...

Hydrophobic tag technology represents an innovative approach for targeted protein degradation, though its application in terms of redox-regulatory proteins like GPX4 presents unique challenges. Our study herein demonstrates the successful development of novel GPX4 degraders through rational conjugation of adamantane hydrophobic tags with the ML162 scaffold. The preferred compound N15 exhibits exceptional antitumor potency against several ferroptosis sensitive cancer cells with IC₅₀ values at single-digit nanomolar level, which exhibited dozens of folds improvement in contrast to the parental compound ML162 and ranked among the most efficient GPX4 degraders ever reported. Moreover, N15 demonstrates degradation potency with a DC₅₀ of 28 nM at 10 h, with rapid and sustained degradation kinetics. Mechanistic studies confirm that N15 mediates GPX4 degradation specifically through the ubiquitin-proteasome system while simultaneously inducing robust ferroptosis. These findings not only establish a novel GPX4 degrader by HyT strategy, but also expand the potential application of this technology for challenging therapeutic targets.