An overview of GPX4-targeting TPDs for cancer therapy.

Abstract

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.