Therapeutic Targets Database
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Target Validation Information
TTD IDTTDC00059
Target NameSerine/threonine-protein kinase 13    
Type of TargetClinical trial target    
Drug Potency against TargetGSK1070916IC50 = 1.5 nM[1]
MK-5108IC50 = 12 nM[2]
VX-689IC50 = 12 nM[2]
SNS-314IC50 = 3.4 nM[1]
AZD1152IC50 = 4.6 nM[1]
VX-680IC50 = 4.6 nM[1]
R763IC50 = 6.8 nM[3]
PHA-739358IC50 = 61 nM[1]
CYC-116IC50 = 69 nM[1]
CYC116IC50 = 69 nM[1]
GSK1070916Ki = 1.45 nM[4]
7-fluoroindirubin-3-acetoximeIC50 = 1000 nM[5]
7-fluoroindirubin-3-oximeIC50 = 1000 nM[5]
PHA-680632IC50 = 120 nM[6]
SU 6656IC50 = 17 nM[7]
6-bromoindirubin-3-oximeIC50 = 200 nM[5]
indirubin-3-oximeIC50 = 300 nM[5]
indirubin-3-methoximeIC50 = 400 nM[5]
7-bromoindirubin-3-acetoximeIC50 = 4500 nM[5]
7-iodoindirubin-3-oximeIC50 = 600 nM[5]
7-bromoindirubin-3-oximeIC50 = 700 nM[5]
indirubin-3-acetoximeIC50 = 700 nM[5]
7-chloroindirubin-3-oximeIC50 = 900 nM[5]
GSK-1070916Ki = 1.5 nM[8]
AZD-1152-HQPA;BarasertibKi = 17 nM[9]
Action against Disease ModelAZD1152Induced growth arrest, polyploidy and promoted apoptosis in various h uMan t uMour xenografts and AML cell lines. Sensitized t uMour cells to radiotherapy in vitro and in vivo.[1]
The Effect of Target Knockout, Knockdown or Genetic VariationsKnock down of aurora C but not aurora B results in cell cycle arrest in early embryonic development.?[10]
We previously isolated Aurora-C/Aie1 in a screen for kinases expressed in mouse sperm and eggs. Here, we show the localization of endogenous Aurora-C and examine its roles during female mouse meiosis. Aurora-C was detected at the centromeres and along the chromosome arms in prometaphase I-metaphase I and was concentrated at centromeres at metaphase II, in which Aurora-C also was phosphorylated at Thr171. During the anaphase I-telophase I transition, Aurora-C was dephosphorylated and relocalized to the midzone and midbody. Microinjection of the kinase-deficient Aurora-C (AurC-KD) mRNA into mouse oocytes significantly inhibited Aurora-C activity and caused multiple defects, including chromosome misalignment, abnormal kinetochore-microtubule attachment, premature chromosome segregation, and cytokinesis failure in meiosis I. Furthermore, AurC-KD reduced Aurora-C and histone H3 phosphorylation and inhibited kinetochore localization of Bub1 and BubR1. Similar effects also were observed in the oocytes injected with INCNEP-delIN mRNAs, in which the Aurora-C binding motif was removed. The most dramatic effect observed in AurC-KD-injected oocytes is cytokinesis failure in meiosis I, resulting in producing large polyploid oocytes, a pattern similar to Aurora-C deficiency h uMan spermatozoa. Surprisingly, we detected no Aurora-B protein in mouse oocytes. We propose that Aurora-C, but not Aurora-B, plays essential roles in female mouse meiosis.[11]
Ref 1Nat Rev Drug Discov. 2009 Jul;8(7):547-66.Cell cycle kinases as therapeutic targets for cancer. To Reference
Ref 2Mol Cancer Ther. 2010 Jan;9(1):157-66. Epub 2010 Jan 6.MK-5108, a highly selective Aurora-A kinase inhibitor, shows antitumor activity alone and in combination with docetaxel. To Reference
Ref 3J Cancer Res Clin Oncol. 2010 Jan;136(1):99-113.Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen. To Reference
Ref 4Mol Cancer Ther. 2009 Jul;8(7):1808-17. Epub 2009 Jun 30.GSK1070916, a potent Aurora B/C kinase inhibitor with broad antitumor activity in tissue culture cells and human tumor xenograft models. To Reference
Ref 5J Med Chem. 2007 Aug 23;50(17):4027-37. Epub 2007 Aug 1.An integrated computational approach to the phenomenon of potent and selective inhibition of aurora kinases B and C by a series of 7-substituted indirubins. To Reference
Ref 6J Med Chem. 2005 Apr 21;48(8):3080-4.Potent and selective Aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition. To Reference
Ref 7Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update. To Reference
Ref 8J Med Chem. 2010 May 27;53(10):3973-4001.Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase. To Reference
Ref 9J Med Chem. 2007 May 3;50(9):2213-24. Epub 2007 Mar 21.Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase. To Reference
Ref 10Development. 2011 Jul;138(13):2661-72. Epub 2011 May 25.Genetic disruption of aurora B uncovers an essential role for aurora C during early mammalian development. To Reference
Ref 11Mol Biol Cell. 2010 Jul 15;21(14):2371-83. Epub 2010 May 19.Aurora-C kinase deficiency causes cytokinesis failure in meiosis I and production of large polyploid oocytes in mice. To Reference



 

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Professor in Department of Pharmacy
National University of Singapore, Singapore


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