title: Biochemical characterization of GSK1070916, a potent and selective inhibitor of Aurora B and Aurora C kinases with an extremely long residence time1.
abstract: 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).
authors.affiliation: Enzymology & Mechanistic Pharmacology, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Anderson
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Lai
authors.forename: Octerloney B
authors.initials: OB
authors.lastname: McDonald
authors.forename: J Darren
authors.initials: JD
authors.lastname: Stuart
authors.forename: Eldridge N
authors.initials: EN
authors.lastname: Nartey
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Hardwicke
authors.forename: Ken
authors.initials: K
authors.lastname: Newlander
authors.forename: Dashyant
authors.initials: D
authors.lastname: Dhanak
authors.forename: Jerry
authors.initials: J
authors.lastname: Adams
authors.forename: Denis
authors.initials: D
authors.lastname: Patrick
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tummino
authors.forename: Jingsong
authors.initials: J
authors.lastname: Yang
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000595:Amino Acid Sequence; D064107:Aurora Kinase B; D064108:Aurora Kinase C; D064127:Aurora Kinases; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D010755:Organophosphates / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000255:Adenosine Triphosphate; D064107:Aurora Kinase B; D064108:Aurora Kinase C; D064127:Aurora Kinases; D002868:Chromosomal Proteins, Non-Histone; D004791:Enzyme Inhibitors; D010755:Organophosphates; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011799:Quinazolines; C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; C083767:INCENP protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576921:AURKB protein, human; C576927:AURKC protein, human; C576924:Aurkb protein, mouse; C576928:Aurkc protein, mouse