AI Article Synopsis
- Chemotherapy-induced myelosuppression (CIM) hinders blood cell production, making it a significant issue in cancer treatment.
- Trilaciclib (TC) is the only FDA-approved CDK4/6 inhibitor that protects bone marrow by stopping the growth of certain cells, and its derivatives show strong potential as effective treatments for CIM.
- Among these, one derivative displayed excellent inhibitory activity, low toxicity, great selectivity, and effective penetration into bone marrow, indicating it could improve treatment outcomes for individuals experiencing myelosuppression from chemotherapy.
Article Abstract
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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| http://dx.doi.org/10.1021/acs.jmedchem.4c02080 | DOI Listing |
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