Discovery of a novel covalent CDK4/6 inhibitor based on palbociclib scaffold

  • Eur J Med Chem. 2021 Jul 5:219:113432. doi: 10.1016/j.ejmech.2021.113432.
Huifang Shan  1 ,  Xinyu Ma  1 ,  Guoyi Yan  2 ,  Meng Luo  1 ,  Xinxin Zhong  1 ,  Suke Lan  3 ,  Jie Yang  1 ,  Yuanyuan Liu  1 ,  Chunlan Pu  1 ,  Yu Tong  4 ,  Rui Li  5
Affiliations
  • 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2. School of Pharmacy, Henan University, Kaifeng 475000, China.
  • 3. College of Chemistry & Environment Protection Engineering, Southwest Minzu University, Chengdu, China.
  • 4. West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan Province, China.
  • 5. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
PMID: 33857728 DOI: 10.1016/j.ejmech.2021.113432
Abstract

Cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved in dynamic regulation of cell cycle, play an indispensable role in controlling the tumor growth. Here, based on the scaffold of palbociclib, we designed and synthesized a series of covalent CDK4/6 inhibitors that targeted amino acid Thr107. The optimized compound C-13 exhibited potent in vitro Anticancer activity against CDK4/6 with high selectivity over CDK4/6. Moreover, C-13 showed significant tumor growth inhibition in MDA-MB-231 tumor xenograft model (TGI of 93.49% at dose of 40 mg/kg) without causing significant weight loss and toxicity during the treatment period.

Keywords
CDK4; CDK6; Cell cycle; Covalent inhibitor; Palbociclib.