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

29 Citations (Scopus)

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

Fingerprint

Aurora Kinases
Phosphotransferases
Phosphorylation
Endoreduplication
Chromosomes
Histones
Centrosome
Chromosome Segregation
Serine
Spindle Apparatus
Cytokinesis
Amplification
Xenopus laevis
Aneuploidy
Mitosis
Carcinogenesis
Molecules
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Andersen, C. B., Wan, Y., Chang, J. W., Riggs, B., Lee, C., Liu, Y., ... Gray, N. S. (2008). Discovery of selective aminothiazole aurora kinase inhibitors. ACS Chemical Biology, 3(3), 180-192. https://doi.org/10.1021/cb700200w

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.

In: ACS Chemical Biology, Vol. 3, No. 3, 20.03.2008, p. 180-192.

Research output: Contribution to journalArticle

Andersen, CB, Wan, Y, Chang, JW, Riggs, B, Lee, C, Liu, Y, Sessa, F, Villa, F, Kwiatkowski, N, Suzuki, M, Nallan, L, Heald, R, Musacchio, A & Gray, NS 2008, 'Discovery of selective aminothiazole aurora kinase inhibitors', ACS Chemical Biology, vol. 3, no. 3, pp. 180-192. https://doi.org/10.1021/cb700200w
Andersen CB, Wan Y, Chang JW, Riggs B, Lee C, Liu Y et al. Discovery of selective aminothiazole aurora kinase inhibitors. ACS Chemical Biology. 2008 Mar 20;3(3):180-192. https://doi.org/10.1021/cb700200w
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. / Discovery of selective aminothiazole aurora kinase inhibitors. In: ACS Chemical Biology. 2008 ; Vol. 3, No. 3. pp. 180-192.
@article{64f79e7e69194037971da30a8a8926b9,
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.}",
year = "2008",
month = "3",
day = "20",
doi = "10.1021/cb700200w",
language = "English",
volume = "3",
pages = "180--192",
journal = "ACS Chemical Biology",
issn = "1554-8929",
publisher = "American Chemical Society",
number = "3",

}

TY - JOUR

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.

UR - http://www.scopus.com/inward/record.url?scp=42449137119&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=42449137119&partnerID=8YFLogxK

U2 - 10.1021/cb700200w

DO - 10.1021/cb700200w

M3 - Article

C2 - 18307303

AN - SCOPUS:42449137119

VL - 3

SP - 180

EP - 192

JO - ACS Chemical Biology

JF - ACS Chemical Biology

SN - 1554-8929

IS - 3

ER -