2. Academic Validation
  3. Discovery of a novel covalent CDK4/6 inhibitor based on palbociclib scaffold

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

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: lirui@scu.edu.cn.
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.

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