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

  • J Med Chem. 2025 Jan 23;68(2):1446-1472. doi: 10.1021/acs.jmedchem.4c02080.
Wei Shi  1 ,  Rong Wang  1 ,  Jianqiang Qian  1 ,  Lu Wang  1 ,  You Li  1 ,  Yahui Mi  1 ,  Zhaotong Jia  1 ,  Mingshi Pan  1 ,  Xiaoqi Zhang  2 ,  Wencai Ye  2 ,  Fei Xiong  3 ,  Xiaolong Hu  1 ,  Hao Wang  1
Affiliations
  • 1. State Key Laboratory of Natural Medicines, Departemnt of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Institute of Traditional Chinese Medicine & Natural Products, Jinan University, Guangzhou 510000, China.
  • 3. State Key Laboratory of Bioelectronics, Jiangsu Laboratory for Biomaterials and Devices, Southeast University, Nanjing 210009, China.
PMID: 39760276 DOI: 10.1021/acs.jmedchem.4c02080
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, 42 displayed potent CDK4/6 inhibitory activity (IC50 = 11 nM), lower cytotoxicity (CC50 > 100 μM) and showed high selectivity among 86 Kinases. Additionally, 42 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, 42 expands the therapeutic applications of CDK4/6i, optimizes the mode of administration, and offers significant translational value and clinical potential.

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