Discovery of selective aminothiazole aurora kinase inhibitors.
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 A 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.
Andersen
Carsten B
CB
Department of Biological Chemistry, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Wan
Yongqin
Y
Chang
Jae W
JW
Riggs
Blake
B
Lee
Christian
C
Liu
Yi
Y
Sessa
Fabio
F
Villa
Fabrizio
F
Kwiatkowski
Nicholas
N
Suzuki
Melissa
M
Nallan
Laxman
L
Heald
Rebecca
R
Musacchio
Andrea
A
Gray
Nathanael S
NS
D000588:Amines / Q000737:chemistry*; D000818:Animals; D064127:Aurora Kinases; D003485:Cyanates / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D014982:Xenopus laevis
D000588:Amines; D003485:Cyanates; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases