Discovery of ML210-Based glutathione peroxidase 4 (GPX4) degrader inducing ferroptosis of human cancer cells

Ferroptosis is an iron-dependent cell death caused by the accumulation of lipid peroxidation. The glutathione peroxidase 4 (GPX4) is an antioxidative enzyme and a major regulator of ferroptosis. Targeting GPX4 has become a promising strategy for cancer therapy. Here in this article, we designed and synthesized a series of GPX4 degraders using ML210 as a warhead. DC-2 among them has been found to have the best degradation activity with the DC50 value of 0.03 μM in HT1080 cells. It also showed an obvious cell growth inhibition effect with the IC50 value of 0.1 μM in HT1080 cells. Mechanism research showed that DC-2 induced GPX4 degradation via the ubiquitin-proteasome pathway and autophagy-lysosome pathway. GPX4 degradation induced by DC-2 could result in the accumulation of ROS and subsequent ferroptosis. The pharmacodynamics study showed that DC-2 could reduce the GPX4 level in HT1080 tumor tissue in mice and has a good safety profile. Above all, a potent and safe compound DC-2 has been found to induce GPX4 degradation and subsequent ferroptosis. This study may lay the foundation for a highly efficient and safe drug with a new mechanism for cancer therapy. [Display omitted] • •DC-2 showed obvious GPX4 degradation activity and cell proliferation inhibition.• •DC-2 resulted in a more effective accumulation of ROS compared to ML210.• •DC-2 induced GPX4 degradation via both UPS and autophagy-lysosome pathway.• •DC-2 could induce obvious in vivo GPX4 degradation effect and has a better safety profile compared to ML210.