Discovery of selective aminothiazole aurora kinase inhibitors

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

doi:10.1021/cb700200w

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Discovery of selective aminothiazole aurora kinase inhibitors

Andersen, C. B., Wan, Y., Chang, J. W., Riggs, B., Lee, C., Liu, Y., et al. (2008). Discovery of selective aminothiazole aurora kinase inhibitors. ACS CHEMICAL BIOLOGY, 3(3), 180-192. doi:10.1021/cb700200w.

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Item Permalink: https://hdl.handle.net/11858/00-001M-0000-0015-3AF2-F Version Permalink: https://hdl.handle.net/11858/00-001M-0000-0015-4EAE-4

Genre: Journal Article

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Andersen, Carsten B.¹, Author
Wan, Yongqin¹, Author
Chang, Jae W.², Author
Riggs, Blake³, Author
Lee, Christian¹, Author
Liu, Yi¹, Author
Sessa, Fabio⁴, Author
Villa, Fabrizio⁴, Author
Kwiatkowski, Nicholas², Author
Suzuki, Melissa⁵, Author
Nallan, Laxman¹, Author
Heald, Rebecca³, Author
Musacchio, Andrea⁶, Author
Gray, Nathanael S.², Author

Affiliations:
1Department of Biological Chemistry, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, ou_persistent22
2Department of Cancer Biology, Dana Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, ou_persistent22
3Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, ou_persistent22
4Department of Experimental Oncology, European Institute of Oncology, Via Adamello, 16-20139 Milan, Italy, ou_persistent22
5Invitrogen Corporation, Madison, Wisconsin 53558, ou_persistent22
6Abt. I:Mechanistische Zellbiologie, Max Planck Institute of Molecular Physiology, Max Planck Society, ou_1753287

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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 angstrom 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.

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Dates: Date issued: 2008

Publication Status: Issued

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Identifiers: ISI: 000254218800007
DOI: 10.1021/cb700200w

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Title: ACS CHEMICAL BIOLOGY

Source Genre: Journal

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Pages: - Volume / Issue: 3 (3) Sequence Number: - Start / End Page: 180 - 192 Identifier: ISSN: 1554-8929