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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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Published in: | Journal of medicinal chemistry 2025-01 |
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Main Authors: | , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites |
Online Access: | Get full text |
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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. |
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ISSN: | 0022-2623 1520-4804 1520-4804 |
DOI: | 10.1021/acs.jmedchem.4c02080 |