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VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo

An Addendum to this article was published on 01 April 2007

Abstract

The Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Aberrant expression and activity of these kinases occur in a wide range of human tumors, and lead to aneuploidy and tumorigenesis. Here we report the discovery of a highly potent and selective small-molecule inhibitor of Aurora kinases, VX-680, that blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types. This compound causes profound inhibition of tumor growth in a variety of in vivo xenograft models, leading to regression of leukemia, colon and pancreatic tumors at well-tolerated doses. Our data indicate that Aurora kinase inhibition provides a new approach for the treatment of multiple human malignancies.

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Figure 1: VX-680 is a potent and selective Aurora kinase inhibitor that blocks proliferation of multiple tumor cell types.
Figure 2: Inhibition of Aurora kinase activity induces tumor cell death.
Figure 3: Aurora kinase inhibition ablates colony formation of primary AML cells.
Figure 4: VX-680 causes accumulation of cells with ≥4N DNA content and inhibits histone H3 phosphorylation on Ser10.
Figure 5: VX-680 induces regression of human HL-60 (AML) and HCT116 (colon) tumors in vivo.
Figure 6: VX-680 inhibits histone H3 phosphorylation and induces apoptosis in tumors in vivo.

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Acknowledgements

We thank S. Renwick, J. Westcott, S. Gladwell, P. Weber, and the Aurora chemistry, crystallography, protein biochemistry, enzymology, DMPK and pharmacology teams for their contributions; and J. Boger, J. Thomson, M. Namchuk and M. Partridge for critical reading of the manuscript.

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Correspondence to Karen M Miller.

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All of the authors are or were employees of, and consultants to, Vertex Pharmaceuticals (Europe) Ltd. or Vertex Pharmaceuticals Inc.

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Harrington, E., Bebbington, D., Moore, J. et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 10, 262–267 (2004). https://doi.org/10.1038/nm1003

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