Biochemical characterization of GSK1070916, a potent and selective inhibitor of Aurora B and Aurora C kinases with an extremely long residence time1

• Published in: Biochemical journal Vol. 420; no. 2; p. 259
• Main Authors: Anderson, Kelly, Lai, Zhihong, McDonald, Octerloney B, Stuart, J Darren, Nartey, Eldridge N, Hardwicke, Mary Ann, Newlander, Ken, Dhanak, Dashyant, Adams, Jerry, Patrick, Denis, Copeland, Robert A, Tummino, Peter J, Yang, Jingsong
• Format: Journal Article
• Language: English
• Published: England 13.05.2009
• Subjects: Adenosine Triphosphate - pharmacology; Amino Acid Sequence; Aurora Kinase B; Aurora Kinase C; Aurora Kinases; Chromosomal Proteins, Non-Histone - antagonists & inhibitors; Chromosomal Proteins, Non-Histone - chemistry; Chromosomal Proteins, Non-Histone - metabolism; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Kinetics; Molecular Sequence Data; Organophosphates - pharmacology; Piperazines - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - chemistry; Protein Serine-Threonine Kinases - metabolism; Quinazolines - pharmacology
• ISSN: 1470-8728
• DOI: 10.1042/BJ20090121

The Aurora kinases AurA, B and C are serine/threonine protein kinases that play essential roles in mitosis and cytokinesis. Among them, AurB is required for maintaining proper chromosome alignment, separation and segregation during mitosis, and regulating a number of critical processes involved in cytokinesis. AurB overexpression has been observed in a variety of cancer cell lines, and inhibition of AurB has been shown to induce tumour regression in mouse xenograft models. In the present study we report the enzymatic characterization of a potent and selective AurB/AurC inhibitor. GSK1070916 is a reversible and ATP-competitive inhibitor of the AurB-INCENP (inner centromere protein) enzyme. It selectively inhibits AurB-INCENP (K(i)*=0.38+/-0.29 nM) and AurC-INCENP (K(i)*=1.5+/-0.4 nM) over AurA-TPX2 (target protein for Xenopus kinesin-like protein 2) (K(i)=490+/-60 nM). Inhibition of AurB-INCENP and AurC-INCENP is time-dependent, with an enzyme-inhibitor dissociation half-life of >480 min and 270+/-28 min respectively. The extremely slow rate of dissociation from the AurB and AurC enzymes distinguishes GSK1070916 from two other Aurora inhibitors in the clinic, AZD1152 and VX-680 (also known as MK-0457).