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VX-680 Inhibits Aurora A and Aurora B Kinase Activity in Human Cells
Rebecca K. Tyler, Natalia Shpiro, Rodolfo Marquez and Patrick A. Eyers
volume 6 | issue 22
15 November 2007Pages: 2846 - 2854
This is an open-access article
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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.
Authors
Rebecca K. Tyler
University of Manchester; Manchester, UK
Natalia Shpiro
University of Dundee; Dundee, UK
Rodolfo Marquez
University of Glasgow; Glasgow, UK
Patrick A. Eyers
University of Manchester; Manchester, UK
This is an open-access article
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.