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Design, synthesis and biological evaluation of ring-fused pyrazoloamino pyridine/pyrimidine derivatives as potential FAK inhibitors.

Authors
  • Xie, Hongming1
  • Lin, Xinglong2
  • Zhang, Yingjun3
  • Tan, Fuxing2
  • Chi, Bo2
  • Peng, Zhihong4
  • Dong, Wanrong1
  • An, Delie5
  • 1 State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China. , (China)
  • 2 The State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co. Ltd, Dongguan 523871, PR China. , (China)
  • 3 The State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co. Ltd, Dongguan 523871, PR China. Electronic address: [email protected] , (China)
  • 4 State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China. Electronic address: [email protected] , (China)
  • 5 State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Aug 09, 2020
Volume
30
Issue
21
Pages
127459–127459
Identifiers
DOI: 10.1016/j.bmcl.2020.127459
PMID: 32784087
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

We report herein the synthesis of novel ring-fused pyrazoloamino pyridine/pyrimidine derivatives as potential FAK inhibitors and the evaluation of pharmaceutical activity against five cancer cell lines (MDA-MB-231, BXPC-3, NCI-H1975, DU145 and 786O). Generally, the majority of compounds displayed strong anti-FAK enzymatic potencies (IC50 < 1 nM) and could effectively inhibit several class of cancer cell lines within the concentration of 3 μM in comparison with GSK2256098 as a reference. Among them, compound 4o is considered to be the most effective due to high sensitivity in antiproliferation. In culture, 4o could not only inhibit FAK Y397 phosphorylation in MDA-MB-231 cell line, but also trigger apoptosis in a dose-dependent manner. Furthermore, computational docking analysis also suggested that 4o and TAE-226 displayed the similar interaction with FAK kinase domain. Copyright © 2020. Published by Elsevier Ltd.

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