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Discovery of Potent and Selective CDK4/6 Inhibitors for the Treatment of Chemotherapy-Induced Myelosuppression

Chemotherapy-induced myelosuppression (CIM) significantly impairs hematopoiesis. Trilaciclib (TC), originally developed for oncology application, is the only FDA-approved CDK4/6 inhibitor for CIM, which effectively protects bone marrow cells by inhibiting their proliferation. In this study, a series...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2025-01
Main Authors: Shi, Wei, Wang, Rong, Qian, Jianqiang, Wang, Lu, Li, You, Mi, Yahui, Jia, Zhaotong, Pan, Mingshi, Zhang, Xiaoqi, Ye, Wencai, Xiong, Fei, Hu, Xiaolong, Wang, Hao
Format: Article
Language:English
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Summary:Chemotherapy-induced myelosuppression (CIM) significantly impairs hematopoiesis. Trilaciclib (TC), originally developed for oncology application, is the only FDA-approved CDK4/6 inhibitor for CIM, which effectively protects bone marrow cells by inhibiting their proliferation. In this study, a series of TC derivatives were designed and synthesized as CDK4/6 inhibitors (CDK4/6i) for alleviating CIM. Among these, displayed potent CDK4/6 inhibitory activity (IC = 11 nM), lower cytotoxicity (CC > 100 μM) and showed high selectivity among 86 kinases. Additionally, possessed strong bone marrow penetration, favorable pharmacokinetic properties, excellent safety profiles, and superior efficacy in mitigating myelosuppression caused by 5-fluorouracil (5-FU) in vivo. In conclusion, as the first oral small-molecule CDK4/6 inhibitor optimized specifically for myelosuppression treatment, expands the therapeutic applications of CDK4/6i, optimizes the mode of administration, and offers significant translational value and clinical potential.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.4c02080