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 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.
authors.affiliation: Department of Biological Chemistry, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors.forename: Carsten B
authors.initials: CB
authors.lastname: Andersen
authors.forename: Yongqin
authors.initials: Y
authors.lastname: Wan
authors.forename: Jae W
authors.initials: JW
authors.lastname: Chang
authors.forename: Blake
authors.initials: B
authors.lastname: Riggs
authors.forename: Christian
authors.initials: C
authors.lastname: Lee
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Fabio
authors.initials: F
authors.lastname: Sessa
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Villa
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kwiatkowski
authors.forename: Melissa
authors.initials: M
authors.lastname: Suzuki
authors.forename: Laxman
authors.initials: L
authors.lastname: Nallan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Heald
authors.forename: Andrea
authors.initials: A
authors.lastname: Musacchio
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: 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
chemical_list: D000588:Amines; D003485:Cyanates; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases