Identification of a lead small-molecule inhibitor of the Aurora kinases using a structure-assisted, fragment-based approach

Steven L. Warner, Sridevi Bashyam, Hariprasad Vankayalapati, David J. Bearss, Haiyong Han, Daniel D. Von Hoff, Laurence H. Hurley

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Aurora A and Aurora B are potential targets for anticancer drug development due to their roles in tumorigenesis and disease progression. To identify small-molecule inhibitors of the Aurora kinases, we undertook a structure-based design approach that used three-dimensional structural models of the Aurora A kinase and molecular docking simulations of chemical entities. Based on these computational methods, a new generation of inhibitors derived from quinazoline and pyrimidine-based tricyclic scaffolds were synthesized and evaluated for Aurora A kinase inhibitory activity, which led to the identification of 4-(6,7-dimethoxy-9H-1, 3,9-triaza-fluoren-4-yl)-piperazine-1-carbothioic acid [4-(pyrimidin-2-ylsulfamoyl)-phenyl]-amide. The lead compound showed selectivity for the Aurora kinases when it was evaluated against a panel of diverse kinases. Additionally, the compound was evaluated in cell-based assays, showing a dose-dependent decrease in phospho-histone H3 levels and an arrest of the cell cycle in the G2-M fraction. Although biological effects were observed only at relatively high concentrations, this chemical series provides an excellent starting point for drug optimization and further development.

Original languageEnglish (US)
Pages (from-to)1764-1773
Number of pages10
JournalMolecular Cancer Therapeutics
Volume5
Issue number7
DOIs
StatePublished - Jul 1 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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