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

摘要

pThe 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 (iK/isubi/sub*=0.38±0.29 nM) and AurC–INCENP (iK/isubi/sub*=1.5±0.4 nM) over AurA–TPX2 (target protein for iXenopus/i kinesin-like protein 2) (iK/isubi/sub=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)./p