Target Validation Information
Target ID T87675
Target Name Aurora kinase A
Target Type
Clinical Trial
Drug Potency against Target CYC116 Drug Info IC50 = 19 nM [1]
AT9283 Drug Info IC50 = 3 nM [1]
AZD-1152-HQPA Drug Info Ki = 1400 nM [2]
PF-03814735 Drug Info IC50 = 5 nM [3]
4-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine Drug Info IC50 = 584 nM [4]
SU-6668 Drug Info IC50 = 850 nM [5]
PHA-739358 Drug Info Ki = 13 nM [6]
MLN8237 Drug Info IC50 = 1 nM [1]
AZD-1152-HQPA Drug Info Ki = 0.36 nM [7]
PHA-739358 Drug Info IC50 = 27 nM [8]
Indirubin-3-acetoxime Drug Info IC50 = 2300 nM [9]
VX-680 Drug Info Ki = 0.6 nM [7]
SNS-314 Drug Info IC50 = 3.4 nM [1]
Indirubin-3-oxime Drug Info IC50 = 4000 nM [9]
ENMD-2076 Drug Info IC50 = 5 nM [1]
R763 Drug Info Ki = 4 nM [10]
MLN8054 Drug Info IC50 = 4 nM [11]
ZM-447439 Drug Info IC50 = 110 nM [12]
6-bromoindirubin-3-oxime Drug Info IC50 = 600 nM [9]
Indirubin-3-methoxime Drug Info IC50 = 4300 nM [9]
7-fluoroindirubin-3-oxime Drug Info IC50 = 2000 nM [9]
Action against Disease Model MLN8237 Active 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). [11] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations To 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 mouseembryonic 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. [1]
References
REF 1End of the line for cannabinoid receptor 1 as an anti-obesity target? An opinion. Nat Rev Drug Discov. 2009 Jul;8(7):594. doi: 10.1038/nrd2775-c1.
REF 2J 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.
REF 3Aurora kinase inhibitors in preclinical and clinical testing. Expert Opin Investig Drugs. 2009 Apr;18(4):379-98. doi: 10.1517/13543780902806392 .
REF 4Bioorg 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.
REF 5Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling. Cancer Res. 2005 Aug 1;65(15):6919-26.
REF 6PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3158-68.
REF 7Aurora-B kinase inhibitors for cancer chemotherapy. Mini Rev Med Chem. 2008 Dec;8(14):1514-25.
REF 8J 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.
REF 9J 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.
REF 10Therapeutic opportunities from muscarinic receptor research. Trends Pharmacol Sci. 2001 Aug;22(8):409-14.
REF 11Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
REF 12J 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.

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