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Discovery of novel and selective CDK4/6 inhibitors by pharmacophore and structure-based virtual screening.

Authors
  • Yuan, Kai1, 2
  • Min, Wenjian1, 2
  • Wang, Xiao1, 2
  • Li, Jiaxing1, 2
  • Kuang, Wenbin1, 2
  • Zhang, Fang1, 2
  • Xie, Shengnan1, 2
  • Yang, Peng1, 2
  • 1 State Key Laboratory of Natural Medicines & Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China. , (China)
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. , (China)
Type
Published Article
Journal
Future Medicinal Chemistry
Publisher
"Future Science, LTD"
Publication Date
Jun 01, 2020
Volume
12
Issue
12
Pages
1121–1136
Identifiers
DOI: 10.4155/fmc-2020-0011
PMID: 32400188
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Aim: CDK4 and 6 are the key initiators in the transition from G1 to S phase in the cell cycle; thus, inhibition of CDK4/6 is a promising strategy for cancer treatment. Materials & methods: The Specs database and an in-house library were screened via the pharmacophore model and LibDock protocol and then the retrieved hits were clustered into 100 clusters. The CDK4/6 inhibitory activity of selected compounds was evaluated by CDK enzymatic assays, followed by chemical optimization of the top hit compound. Results & conclusion: The integration of pharmacophores and molecular docking offered us an effective method to discover the novel CDK4/6 inhibitor 10 and further chemical optimization led to the highly selective and potent CDK4/6 inhibitor 18, which exhibited potential for the treatment of multiple myeloma.

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