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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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    • "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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