Target Validation Information | |||||
---|---|---|---|---|---|
Target ID | T46781 | ||||
Target Name | Aurora kinase B | ||||
Target Type | Clinical Trial |
||||
Drug Potency against Target | R763 | Drug Info | IC50 = 4.8 nM | [537610] | |
VX-680 | Drug Info | Ki = 18 nM | [526974] | ||
GSK1070916 | Drug Info | IC50 = 0.38 nM | [537564] | ||
SNS-314 | Drug Info | IC50 = 31 nM | [537564] | ||
PF-03814735 | Drug Info | Ki = 0.8 nM | [553038] | ||
CYC116 | Drug Info | IC50 = 19 nM | [537564] | ||
SU-6668 | Drug Info | IC50 = 8 nM | [552727] | ||
MK-5108 | Drug Info | IC50 = 14 nM | [553013] | ||
AZD-1152-HQPA | Drug Info | IC50 = 3.7 nM | [537564] | ||
PHA-739358 | Drug Info | IC50 = 79 nM | [537564] | ||
AT9283 | Drug Info | IC50 = 3 nM | [537564] | ||
Action against Disease Model | PHA-739358 | PHA-739358 inhibits Aurora kinases in a biochemical assay with IC50 79 nmol/L for Aurora A, B, and C, respectively. | [537564] | Drug Info | |
The Effect of Target Knockout, Knockdown or Genetic Variations | Here 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 | [537610] | |||
References | |||||
Ref 537610 | Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen. J Cancer Res Clin Oncol. 2009 Jul 17. | ||||
Ref 526974 | Nat 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. | ||||
Ref 537564 | Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66. | ||||
Ref 537564 | Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66. | ||||
Ref 553038 | PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy. Mol Cancer Ther. 2010 Apr;9(4):883-94. doi: 10.1158/1535-7163.MCT-09-0915. Epub 2010 Mar 30. | ||||
Ref 537564 | Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66. | ||||
Ref 537564 | Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66. | ||||
Ref 552727 | Molecular design and clinical development of VEGFR kinase inhibitors. Curr Top Med Chem. 2007;7(14):1379-93. | ||||
Ref 553013 | MK-5108, a highly selective Aurora-A kinase inhibitor, shows antitumor activity alone and in combination with docetaxel. Mol Cancer Ther. 2010 Jan;9(1):157-66. doi: 10.1158/1535-7163.MCT-09-0609. Epub 2010 Jan 6. | ||||
Ref 537564 | Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66. | ||||
Ref 537564 | Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66. | ||||
Ref 537564 | Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66. |
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