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...

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Veröffentlicht in:Journal of medicinal chemistry 2024-02, Vol.67 (4), p.2758-2776
Hauptverfasser: Zhu, Jiangmin, Cai, Yuxing, Kong, Min, Li, Yalin, Zhu, Ling, Zhang, Jianfei, Yu, Zhanpeng, Xu, Shishu, Hong, Lihong, Chen, Chen, Luo, Jianguang, Kong, Lingyi
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Sprache:eng
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Zusammenfassung: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.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.3c01890