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

doi:10.1021/cb700200w

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

Istituto Europeo di Oncologia

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	180-192
Number of pages	13
Journal	ACS Chemical Biology
Volume	3
Issue number	3
DOIs	https://doi.org/10.1021/cb700200w
Publication status	Published - Mar 20 2008

ASJC Scopus subject areas

Biochemistry
Molecular Medicine

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10.1021/cb700200w

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title = "Discovery of selective aminothiazole aurora kinase inhibitors",

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 {\AA} 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.",

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

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doi = "10.1021/cb700200w",

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T1 - Discovery of selective aminothiazole aurora kinase inhibitors

AU - Andersen, Carsten B.

AU - Wan, Yongqin

AU - Chang, Jae W.

AU - Riggs, Blake

AU - Lee, Christian

AU - Liu, Yi

AU - Sessa, Fabio

AU - Villa, Fabrizio

AU - Kwiatkowski, Nicholas

AU - Suzuki, Melissa

AU - Nallan, Laxman

AU - Heald, Rebecca

AU - Musacchio, Andrea

AU - Gray, Nathanael S.

PY - 2008/3/20

Y1 - 2008/3/20

N2 - 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.

AB - 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.

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Discovery of selective aminothiazole aurora kinase inhibitors

Abstract

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