Therapeutic Targets Database
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Target Validation Information
TTD IDTTDC00006
Target NameAurora kinase A    
Type of TargetClinical trial target    
Drug Potency against TargetMK-5108IC50 = 0.064 nM[1]
VX-689IC50 = 0.064 nM[1]
VX-680IC50 = 0.6 nM[2]
VX-680IC50 = 0.7 nM[3]
VX-680IC50 = 0.7 nM[4]
MLN8237IC50 = 1 nM[3]
MLN8237IC50 = 1 nM[4]
PHA-739358IC50 = 13 nM[5]
PHA-739358IC50 = 13 nM[3]
PHA-739358IC50 = 13 nM[4]
ENMD-2076IC50 = 14 nM[3]
VX-680IC50 = 160 nM[5]
CYC116IC50 = 19 nM[4]
AT-9283IC50 = 3 nM[6]
AT9283IC50 = 3 nM[4]
AT9283IC50 = 3 nM[3]
SNS-314IC50 = 3.4 nM[4]
AZD1152IC50 = 3.7 nM[4]
MLN8054IC50 = 4 nM[4]
MLN8054IC50 = 4 nM[3]
MLN8054IC50 = 4 nM[2]
R763IC50 = 4 nM[7]
CYC-116IC50 = 44 nM[3]
CYC116IC50 = 44 nM[3]
ENMD-2076IC50 = 5 nM[4]
PF-03814735IC50 = 5 nM[8]
SU-6668IC50 = 850 nM[9]
SNS-314IC50 = 9 nM[3]
AZD1152Ki = 0.36 nM[10]
VX-680Ki = 0.6 nM[11]
VX-680Ki = 0.6 nM[12]
VX-680Ki = 0.6 nM[10]
PHA-739358Ki = 13 nM[13]
AT-9283Ki = 3 nM[14]
AT9283Ki = 3 nM[15]
R763Ki = 4 nM[16]
PF-03814735Ki = 5 nM[17]
CYC-116Ki = 8 nM[18]
ZM-447439IC50 = 110 nM[19]
GSK-1070916IC50 = 1259 nM[20]
7-fluoroindirubin-3-oximeIC50 = 2000 nM[21]
indirubin-3-acetoximeIC50 = 2300 nM[21]
PHA-680632IC50 = 27 nM[22]
indirubin-3-oximeIC50 = 4000 nM[21]
indirubin-3-methoximeIC50 = 4300 nM[21]
4-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridineIC50 = 584 nM[23]
6-bromoindirubin-3-oximeIC50 = 600 nM[21]
AZD-1152-HQPA;BarasertibKi = 1400 nM[24]
Action against Disease ModelMLN8237Active against neuroblastoma xenografts in vivo (more than standard chemotherapy) and ALL xenografts. Induced cytotoxicity and cell cycle arrest in G2-M phase in multiple myeloma cellular models (at 0.25 mM).[3]
The Effect of Target Knockout, Knockdown or Genetic VariationsTo understand the physiological functions of Aurora A, we generated Aurora A knock-out mice. Aurora A null mice die early during embryonic development before the 16-cell stage. These Aurora A null embryos have defects in mitosis, particularly in spindle assembly, supporting critical functions of Aurora A during mitotic transitions. Interestingly, Aurora A heterozygosity results in a significantly increased t uMor incidence in mice, suggesting that Aurora A may also act as a haploinsufficient t uMor suppressor. Consistently, Aurora A heterozygous mouse embryonic fibroblasts have higher rates of aneuploidy. We further discovered that VX-680, an Aurora kinase inhibitor currently in phase II clinical trials for cancer treatment, could induce aneuploidy in wild type mouse embryonic fibroblasts. We conclude that a balanced Aurora A level is critical for maintaining genomic stability and one needs to be fully aware of the potential side effects of anti-cancer therapy based on the use of Aurora A-specific inhibitors.[25]
Ref 1Mol 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 2Nat Biotechnol. 2008 Jan;26(1):127-32.A quantitative analysis of kinase inhibitor selectivity. To Reference
Ref 3Nat Rev Drug Discov. 2009 Jul;8(7):547-66.Cell cycle kinases as therapeutic targets for cancer. To Reference
Ref 4Nat Rev Drug Discov. 2009 Jul;8(7):594.End of the line for cannabinoid receptor 1 as an anti-obesity target? An opinion. To Reference
Ref 5Curr Top Med Chem. 2008;8(10):905-21.Inhibitors of ABL and the ABL-T315I mutation. To Reference
Ref 6Company report from astex To Reference
Ref 7J 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 8Expert Opin Investig Drugs. 2009 Apr;18(4):379-98.Aurora kinase inhibitors in preclinical and clinical testing. To Reference
Ref 9Cancer Res. 2005 Aug 1;65(15):6919-26.Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling. To Reference
Ref 10Mini Rev Med Chem. 2008 Dec;8(14):1514-25.Aurora-B kinase inhibitors for cancer chemotherapy. To Reference
Ref 11Nat Med. 2004 Mar;10(3):262-7. Epub 2004 Feb 22.VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. To Reference
Ref 12Curr Top Med Chem. 2005;5(8):807-21.Progress in the development of selective inhibitors of aurora kinases. To Reference
Ref 13Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3158-68.PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer. To Reference
Ref 14J Med Chem. 2009 Jan 22;52(2):379-88.Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. To Reference
Ref 15Chapter 10 Advances in the Discovery of I?B Kinase Inhibitors. Annual Reports in Medicinal Chemistry. Volume 43, 2008, Pages 155-170 To Reference
Ref 16Trends Pharmacol Sci. 2001 Aug;22(8):409-14.Therapeutic opportunities from muscarinic receptor research. To Reference
Ref 17Mol Cancer Ther. 2010 Apr;9(4):883-94. Epub 2010 Mar 30.PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy. To Reference
Ref 18J Med Chem. 2010 Jun 10;53(11):4367-78.Discovery of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors. To Reference
Ref 19J Med Chem. 2006 Aug 10;49(16):4805-8.Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. To Reference
Ref 20J 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 21J 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 22J 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 23Bioorg Med Chem Lett. 2010 Apr 15;20(8):2552-5. Epub 2010 Mar 1.Discovery of a new series of Aurora inhibitors through truncation of GSK1070916. To Reference
Ref 24J 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 25J Biol Chem. 2008 Nov 14;283(46):31785-90. Epub 2008 Sep 17.Aurora A is essential for early embryonic development and tumor suppression. To Reference



 

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