Biochemical characterization of GSK1070916, a potent and selective inhibitor of Aurora B and Aurora C kinases with an extremely long residence time1.
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).
Anderson
Kelly
K
Enzymology & Mechanistic Pharmacology, GlaxoSmithKline, Collegeville, PA 19426, USA.
Lai
Zhihong
Z
McDonald
Octerloney B
OB
Stuart
J Darren
JD
Nartey
Eldridge N
EN
Hardwicke
Mary Ann
MA
Newlander
Ken
K
Dhanak
Dashyant
D
Adams
Jerry
J
Patrick
Denis
D
Copeland
Robert A
RA
Tummino
Peter J
PJ
Yang
Jingsong
J
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
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