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

Nat Med. 2004 Mar;10(3):262-7. doi: 10.1038/nm1003. Epub 2004 Feb 22.

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.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Aurora Kinases
  • Cell Cycle / physiology
  • Cell Line, Tumor
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Histones / metabolism
  • Humans
  • Mice
  • Mice, Nude
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Piperazines / therapeutic use*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Rats

Substances

  • Enzyme Inhibitors
  • Histones
  • Piperazines
  • VX680
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases