Discovery of selective aminothiazole aurora kinase inhibitors

ACS Chem Biol. 2008 Mar 20;3(3):180-92. doi: 10.1021/cb700200w. Epub 2008 Feb 29.

Abstract

Aurora family kinases regulate important events during mitosis including centrosome maturation and separation, mitotic spindle assembly, and chromosome segregation. Misregulation of Aurora kinases due to genetic amplification and protein overexpression results in aneuploidy and may contribute to tumorigenesis. Here we report the discovery of new small molecule aminothiazole inhibitors of Aurora kinases with exceptional kinase selectivity and report a 1.7 A cocrystal structure with the Aurora B:INCENP complex from Xenopus laevis. The compounds recapitulate the hallmarks of Aurora kinase inhibition, including decreased histone H3 serine 10 phosphorylation, failure to complete cytokinesis, and endoreduplication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemistry*
  • Animals
  • Aurora Kinases
  • Cyanates / chemistry
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism*
  • Sensitivity and Specificity
  • Structure-Activity Relationship
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology*
  • Xenopus laevis

Substances

  • Amines
  • Cyanates
  • Protein Kinase Inhibitors
  • Thiazoles
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases