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 537610Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen. J Cancer Res Clin Oncol. 2009 Jul 17.
Ref 526974Nat 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 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 553038PF-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 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 552727Molecular design and clinical development of VEGFR kinase inhibitors. Curr Top Med Chem. 2007;7(14):1379-93.
Ref 553013MK-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 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.

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