Elucidating Binding Selectivity in Cyclin-Dependent Kinases 4, 6, and 9: Development of Highly Potent and Selective CDK4/9 Inhibitors

作者：Chenran Jiang, Yuxin Ye, Wei Kang, Jinglei Yang, Zhipeng He, Qixiong Cao, Chenshan Lian, Yajie Xing, Qianqian Yang, Juan Zhao, Shuqiong Pan, Meixi Feng, Chunli Song, Zhihong Liu, Rui Wang, Feng Yin, Yun‐Dong Wu, Jiean Chen, Yong Huang · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.4c01686 · 被引用次数：10 · 研究领域：Advanced Breast Cancer Therapies、Cancer-related cognitive impairment studies、Cancer-related Molecular Pathways

breast cancer but face limitations due to therapeutic resistance and hematological toxicity, particularly from strong CDK6 inhibition. To address these challenges, designing selective inhibitors targeting specific cyclin-dependent kinases (CDK) members could offer clinical advantages and broaden CDK inhibitor indications. However, the highly conserved binding pockets of CDKs complicate selective targeting. This study leverages in silico modeling and structural analysis of cocrystal data to identify subtle differences in key CDK binding pockets. Notably, a sequence difference in the αD-helix motif between CDK4 and CDK6 provides a targetable "sweet spot" for selectivity. By incorporating a 1,4-trans-cyclohexanediamine side chain, we designed molecules that favor interactions with CDK4 over CDK6 and explored potential dual CDK4/9 inhibition. This approach yielded a lead compound with distinct in vitro selectivity and promising in vivo pharmacokinetics, offering valuable insights for the development of selective next-generation CDK inhibitors.