Discovery of selective aminothiazole aurora kinase inhibitors

Carsten B. Andersen, Yongqin Wan, Jae W. Chang, Blake Riggs, Christian Lee, Yi Liu, Fabio Sessa, Fabrizio Villa, Nicholas Kwiatkowski, Melissa Suzuki, Laxman Nallan, Rebecca Heald, Andrea Musacchio, Nathanael S. Gray

Research output: Contribution to journalArticle

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 Å 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.

Original languageEnglish
Pages (from-to)180-192
Number of pages13
JournalACS Chemical Biology
Volume3
Issue number3
DOIs
Publication statusPublished - Mar 20 2008

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Andersen, C. B., Wan, Y., Chang, J. W., Riggs, B., Lee, C., Liu, Y., Sessa, F., Villa, F., Kwiatkowski, N., Suzuki, M., Nallan, L., Heald, R., Musacchio, A., & Gray, N. S. (2008). Discovery of selective aminothiazole aurora kinase inhibitors. ACS Chemical Biology, 3(3), 180-192. https://doi.org/10.1021/cb700200w