VX-680 Inhibits Aurora A and Aurora B Kinase Activity in Human Cells

Faculty of Life Sciences, University of Manchester, Manchester, UK.
Cell cycle (Georgetown, Tex.) (Impact Factor: 5.01). 09/2007; 6(22):2846-54. DOI: 10.4161/cc.6.22.4940
Source: PubMed

ABSTRACT VX-680, also known as MK-0457, is a member of a diverse group of small molecules that inhibit the Aurora kinases, and has shown significant potential as an anti-cancer agent. In keeping with many protein kinase inhibitors, this compound is not a monospecific agent, and its cellular specificity remains largely unknown. In cells, VX-680 blocks mitotic Histone H3 phosphorylation and induces polyploidy and apoptosis, consistent with inhibition of the mitotic protein kinase Aurora B. In this study, we have investigated the effects of VX-680 in proliferating human cancer cells, and demonstrate that it blocks the phosphorylation and activation of both Aurora A and B. Additionally, VX-680 suppresses the phosphorylation of specific substrates of each enzyme, including the Aurora A target TACC3 on Ser558. Exposure to VX-680 induces a monopolar spindle phenotype, delays mitotic progression and rapidly overrides the spindle assembly checkpoint in the presence of spindle poisons. VX-680 also exhibits potent cytotoxicity when compared to the well documented Aurora B inhibitor ZM447439. Taken together, these data identify Aurora A and Aurora B as dual intracellular targets of VX-680.

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Available from: Patrick A Eyers, Aug 28, 2015
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    • "These inhibitors often have potencies of nM IC50 values against cognate protein kinases in cell-free assay (19), and they are considered highly selective. For example, VX-608 has an IC50 value of 36 nM against Aurora kinase A in cell-free assay (20). However, Bain et al (19) demonstrated that all of the small-molecule protein kinase inhibitors that they tested had substantial off-target effects on protein kinases other than their cognate kinases. "
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    • "We have also shown herein that depletion of STK31 induces apoptosis. STK31 might serve as a potential target for cancer treatment given that inhibitory compounds targeting cell cycle kinases such as Polo-like kinase 1, Aurora-A and Aurora-B have been quite successful in treating cancers [12], [15], [39]. "
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    • "To identify possible kinases responsible for the mitotic phosphorylation of TIN2, unsynchronized or nocodazole-arrested HeLa cells expressing wild-type Flag-TIN2 were treated with either vehicle alone (DMSO) as a control or small molecular compounds known to inhibit common mitotic kinases. Specifically, cells were treated with 10µm BI-D1870, which is reported to inhibit the family of p90 ribosome S6 kinases (RSK) [24], [25], 10nM BI 2536, which is reported to inhibit Polo-like kinase 1 [26], 10µm VX-680, which is reported to inhibit the family of Aurora kinases [25], [27], and lastly, 10µm H-89, which is reported to inhibit protein kinase A [25]. Derived lysates were then subjected to immunoprecipitation with an anti-Flag antibody followed by immunoblot with either the anti-Phos-S330 antibody to detect phosphorylated TIN2 or an anti-TIN2 antibody to detect total TIN2 protein as a loading control. "
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