GPX4 inhibitors (Hainan University)

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 T_m value of 6.2 °C. Furthermore, (R)-9i showed strong binding affinity against GPX4 (K_D = 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.

Ferroptosis is a newly identified form of regulated, non-apoptotic cell death caused by iron-dependent phospholipid peroxidation. Glutathione peroxidase 4 (GPX4) inactivation-induced ferroptosis is an efficient antitumor treatment. Currently, several GPX4 inhibitors have been identified. However, these inhibitors exhibit low selectivity and poor pharmacokinetic properties that preclude their clinical use. Targeted protein degradation (TPD) is an efficient strategy for discovering drugs and has unique advantages over target protein inhibition. Given GPX4's antitumor effects and the potential of TPD, researchers have explored GPX4-targeting TPDs, which outperform conventional inhibitors in several aspects, such as increased selectivity, strong anti-proliferative effects, overcoming drug resistance, and enhancing drug-like properties. In this review, we comprehensively summarize the progress in GPX4-targeting TPDs. In addition, we reviewed the changes and challenges related to the development of GPX4-targeting TPDs for cancer therapy.