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

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

  • J Med Chem. 2025 Jan 23;68(2):1499-1510. doi: 10.1021/acs.jmedchem.4c01686.
Chenran Jiang 1 2,  Yuxin Ye 2,  Wei Kang 2,  Jinglei Yang 1,  Zhipeng He 2,  Qixiong Cao 2,  Chenshan Lian 2,  Yajie Xing 3,  Qianqian Yang 2,  Juan Zhao 2,  Shuqiong Pan 2,  Meixi Feng 2,  Chunli Song 2,  Zhihong Liu 2,  Rui Wang 2,  Feng Yin 2,  Yun-Dong Wu 1 4 5 6,  Jiean Chen 2,  Yong Huang 3
Affiliations

Affiliations

  • 1 Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
  • 2 Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen 518118, China.
  • 3 Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong SAR 999077, China.
  • 4 Key Laboratory of Computational Chemistry and Drug Design, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
  • 5 Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen 518132, China.
  • 6 College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
PMID: 39754579 DOI: 10.1021/acs.jmedchem.4c01686
Abstract

CDK4/6 inhibitors are effective in treating HR+/HER2- 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-170815
    CDK4/9 Inhibitor
    CDK