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

doi:10.1016/j.ejmech.2016.08.026

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

Eur J Med Chem. 2016 Nov 29:124:186-199. doi: 10.1016/j.ejmech.2016.08.026. Epub 2016 Aug 16.

Authors

Affiliations

¹ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC; Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan, ROC.
² Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
³ Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan, ROC. Electronic address: bjuang@mx.nthu.edu.tw.
⁴ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC; Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan, ROC. Electronic address: hphsieh@nhri.org.tw.

PMID: 27573544
DOI: 10.1016/j.ejmech.2016.08.026

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.

Keywords: Aurora kinases inhibitor; Indazole; Isoform selectivity; Ligand efficiency; Structure-activity relationship (SAR).

MeSH terms

Aurora Kinase A / antagonists & inhibitors*
Aurora Kinase A / chemistry
Cell Proliferation / drug effects
Computer Simulation*
Drug Design*
HCT116 Cells
Humans
Indazoles / chemistry*
Indazoles / pharmacology*
Molecular Docking Simulation
Protein Conformation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*

Substances

Indazoles
Protein Kinase Inhibitors
Aurora Kinase A