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 (Ki*=0.38±0.29 nM) and AurC–INCENP (Ki*=1.5±0.4 nM) over AurA–TPX2 (target protein for Xenopus kinesin-like protein 2) (Ki=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).
Biochemical characterization of GSK1070916, a potent and selective inhibitor of Aurora B and Aurora C kinases with an extremely long residence time1
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Kelly Anderson, Zhihong Lai, Octerloney B. Mcdonald, J. Darren Stuart, Eldridge N. Nartey, Mary Ann Hardwicke, Ken Newlander, Dashyant Dhanak, Jerry Adams, Denis Patrick, Robert A. Copeland, Peter J. Tummino, Jingsong Yang; Biochemical characterization of GSK1070916, a potent and selective inhibitor of Aurora B and Aurora C kinases with an extremely long residence time1. Biochem J 1 June 2009; 420 (2): 259–265. doi: https://doi.org/10.1042/BJ20090121
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