Design, Synthesis, and Biological Evaluation for First GPX4 and CDK Dual Inhibitors

The coexistence of Ferroptosis and other modes of death has great advantages in the treatment of cancers. A series of Glutathione Peroxidase 4 (GPX4) and cyclin-dependent kinase (CDK) dual inhibitors were designed and synthesized, given the synergistic Anticancer effect of ML162 (GPX4 inhibitor) in combination with indirubin-3'-oxime (IO) (CDK Inhibitor). Compound B9 exhibited the highest potential cytotoxic activity against all four cell lines and displayed excellent inhibitory activity against GPX4 (IC₅₀ = 542.5 ± 0.9 nM) and selective inhibition of CDK 4/6 (IC₅₀ = 191.2 ± 8.7, 68.1 ± 1.4 nM). Mechanism research showed that B9 could simultaneously induce Ferroptosis and arrest cells at the G1 phase in both MDA-MB-231 cells and HCT-116 cells. Compared with ML162 and IO, B9 showed much stronger Cancer cell growth inhibition in vivo. These results proved that developing potent GPX4/CDK dual inhibitors is a promising strategy for the malignant Cancer therapy.