Discovery of novel inhibitors of Aurora kinases with indazole scaffold: In silico fragment-based and knowledge-based drug design

Chun Feng Chang, Wen Hsing Lin, Yi Yu Ke, Yih Shyan Lin, Wen Chieh Wang, Chun Hwa Chen, Po Chu Kuo, John T.A. Hsu, Biing Jiun Uang, Hsing Pang Hsieh

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Aurora kinases have emerged as important anticancer targets so that there are several inhibitors have advanced into clinical study. Herein, we identified novel indazole derivatives as potent Aurora kinases inhibitors by utilizing in silico fragment-based approach and knowledge-based drug design. After intensive hit-to-lead optimization, compounds 17 (dual Aurora A and B), 21 (Aurora B selective) and 30 (Aurora A selective) possessed indazole privileged scaffold with different substituents, which provide sub-type kinase selectivity. Computational modeling helps in understanding that the isoform selectivity could be targeted specific residue in the Aurora kinase binding pocket in particular targeting residues Arg220, Thr217 or Glu177.

Original languageEnglish
Pages (from-to)186-199
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume124
DOIs
Publication statusPublished - 2016

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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