Discovery of novel inhibitors of Aurora kinases with indazole scaffold: In silico fragment-based and knowledge-based drug design.
Basic Information
ID: ALA3871274
Journal: Eur J Med Chem
Title: Discovery of novel inhibitors of Aurora kinases with indazole scaffold: In silico fragment-based and knowledge-based drug design.
Authors: Chang CF, Lin WH, Ke YY, Lin YS, Wang WC, Chen CH, Kuo PC, Hsu JTA, Uang BJ, Hsieh HP.
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.
CiteXplore: 27573544
DOI: 10.1016/j.ejmech.2016.08.026
Patent ID: ┄