Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer

  • J Med Chem. 2022 Nov 24;65(22):15102-15122. doi: 10.1021/acs.jmedchem.2c00947.
Weijiao Chen  1 ,  Minghui Ji  1 ,  Hao Cheng  1  2 ,  Mingming Zheng  1 ,  Fei Xia  1 ,  Wenjian Min  1 ,  Huanaoyu Yang  1 ,  Xiao Wang  1 ,  Liping Wang  1 ,  Lijuan Cao  2 ,  Kai Yuan  1 ,  Peng Yang  1  3
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 2. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing 210009, China.
  • 3. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 36350721 DOI: 10.1021/acs.jmedchem.2c00947
Abstract

Breast Cancer is the most common tumor in women, and selective cyclin-dependent kinase (CDK) 4/6 inhibitors played an important role in the treatment of breast Cancer. Therefore, discovering selective CDK4/6 inhibitors with great safety and potent efficacy is beneficial for the breast Cancer treatment. In our work, the lead compound 8 was identified through virtual screening; then, systematic structural optimization was conducted to afford 42, which exhibited strong inhibition on CDK4/6 and showed high selectivity among 205 kinases. 42 possessed excellent safety profiles (LD50 > 5,000 mg/kg), favorable pharmacokinetic properties (F % = 43%), and potent efficacy in reducing the burden of breast Cancer in vivo. In conclusion, we offered a highly selective CDK4/6 inhibitor, which could be used as a great candidate for further preclinical studies of breast Cancer.

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