Discovery of selective aminothiazole aurora kinase inhibitors

被引：37

作者：

Andersen, Carsten B. ^{[2
]}

Wan, Yongqin ^{[2
]}

Chang, Jae W. ^{[1
]}

Riggs, Blake ^{[4
]}

Lee, Christian ^{[2
]}

Liu, Yi ^{[2
]}

Sessa, Fabio ^{[3
]}

Villa, Fabrizio ^{[3
]}

Kwiatkowski, Nicholas ^{[1
]}

Suzuki, Melissa ^{[5
]}

Nallan, Laxman ^{[2
]}

Heald, Rebecca ^{[4
]}

Musacchio, Andrea ^{[3
]}

Gray, Nathanael S. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol,Dept Canc Biol, Boston, MA 02115 USA

[2] Novartis Res Fdn, Gen Inst, Dept Biol Chem, San Diego, CA 92121 USA

[3] European Inst Oncol, Dept Expt Oncol, I-20139 Milan, Italy

[4] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA

[5] Invitrogen Corp, Madison, WI 53558 USA

来源：

ACS CHEMICAL BIOLOGY | 2008年 / 3卷 / 03期

关键词：

D O I：

10.1021/cb700200w

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：180 / 192

页数：13

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