期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 124, 期 -, 页码 186-199出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.08.026
关键词
Aurora kinases inhibitor; Indazole; Ligand efficiency; Isoform selectivity; Structure-activity relationship (SAR)
资金
- National Health Research Institutes
- Ministry of Science and Technology, Taiwan [MOST-101-2113-M-400-002-MY4, MOST-103-2325-B-400 -021]
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. (C) 2016 Elsevier Masson SAS. All rights reserved.
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