Therapeutic Targets Database
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Target Validation Information
TTD IDTTDC00139
Target NameSerine/threonine protein kinase 12    
Type of TargetClinical trial target    
Drug Potency against TargetGSK1070916IC50 = 0.38 nM[1]
PF-03814735IC50 = 0.8 nM[2]
MK-5108IC50 = 14 nM[3]
VX-689IC50 = 14 nM[3]
VX-680IC50 = 18 nM[1]
CYC-116IC50 = 19 nM[1]
CYC116IC50 = 19 nM[1]
SU-6668IC50 = 20 nM[4]
AT-9283IC50 = 3 nM[5]
AT9283IC50 = 3 nM[1]
AZD1152IC50 = 3.7 nM[1]
SNS-314IC50 = 31 nM[1]
R763IC50 = 4.8 nM[6]
SU-6668IC50 = 47 nM[7]
SU-6668IC50 = 60 nM[8]
PHA-739358IC50 = 79 nM[1]
SU-6668IC50 = 8 nM[9]
GSK1070916Ki = 0.38 nM[10]
GSK1070916Ki = 0.38 nM[7]
PF-03814735Ki = 0.8 nM[11]
VX-680Ki = 18 nM[12]
AT-9283Ki = 3 nM[13]
AT9283Ki = 3 nM[14]
R763Ki = 4.8 nM[15]
SU-6668Ki = 47 nM[16]
PHA-739358Ki = 79 nM[17]
CYC-116Ki = 9 nM[18]
Action against Disease ModelPHA-739358PHA-739358 inhibits Aurora kinases in a biochemical assay with IC50 79 nmol/L for Aurora A, B, and C, respectively.[1]
The Effect of Target Knockout, Knockdown or Genetic VariationsHere we describe the expression and distribution patterns of the three kinases in mouse testis using in situ hybridization and immunohistochemistry. Importantly, the localization of Aurora-B is tightly regulated during spermatogenesis, whereas Aurora-C expression appears to be testis specific. To address the function of Aurora-B in spermatogenesis, we have generated transgenic mice using a pachytene-stage-specific promoter driving the expression of either wild-type Aurora-B or an inactive form of the kinase. Expression of the inactive Aurora-B results in abnormal spermatocytes, increased apoptosis, spermatogenic arrest, and subfertility defects. The function of Aurora-C may also be targeted in the Aurora-B transgenic mutants. To address the function of Aurora-C in testis, we generated Aurora-C knockout mice by homologous recombination. Remarkably, Aurora-C null mice were viable, yet the males had compromised fertility. Aurora-C mutant sperm display abnormalities that included heterogenous chromatin condensation, loose acrosomes, and blunted heads. These findings indicate that Aurora-B and Aurora-C serve specialized functions in mammalian spermatogenesis[19]
Ref 1Nat Rev Drug Discov. 2009 Jul;8(7):547-66.Cell cycle kinases as therapeutic targets for cancer. To Reference
Ref 2Expert Opin Investig Drugs. 2009 Apr;18(4):379-98.Aurora kinase inhibitors in preclinical and clinical testing. To Reference
Ref 3Mol 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 4Expert Opin Investig Drugs. 2008 Jul;17(7):1013-28.Therapeutic potential of novel selective-spectrum kinase inhibitors in oncology. To Reference
Ref 5Company report from astex To Reference
Ref 6J 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 7Nat 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 8Curr Top Med Chem. 2002 Sep;2(9):973-1000.Small molecule inhibitors of KDR (VEGFR-2) kinase: an overview of structure activity relationships. To Reference
Ref 9Curr Top Med Chem. 2007;7(14):1379-93.Molecular design and clinical development of VEGFR kinase inhibitors. To Reference
Ref 10Mol 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 11Mol 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 12Nat 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 13J 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 14Biochemistry. 1999 Sep 7;38(36):11597-603.NVP-DPP728 (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)- pyrrolidine), a slow-binding inhibitor of dipeptidyl peptidase IV. To Reference
Ref 15Trends Pharmacol Sci. 2001 Aug;22(8):409-14.Therapeutic opportunities from muscarinic receptor research. To Reference
Ref 16Cancer 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 17Mol 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 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 19Mol Endocrinol. 2007 Mar;21(3):726-39. Epub 2006 Dec 27.Differential functions of the Aurora-B and Aurora-C kinases in mammalian spermatogenesis. To Reference



 

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