Difluoro analogue of UCS15A triggers activation of exogenously expressed c-Src in HCT 116 human colorectal carcinoma cells

J Enzyme Inhib Med Chem. 2007 Oct;22(5):638-46. doi: 10.1080/14756360701485760.

Abstract

UCS 15A, an antibiotic produced by Streptomyces sp., has been reported to specifically disrupt SH3 domain-mediated interactions in eukaryotic cells. Interestingly, in the case of the non-receptor tyrosine kinase Src, UCS15A was effective in suppressing the SH3 domain-mediated intermolecular rather than intramolecular interactions, and thus prevented Src interactions with certain downstream effectors without affecting Src kinase activity. Here the synthesis of a novel difluoro analogue of UCS15A is described. The effects of this compound (8) on Src activity were tested in HCT 116 colorectal carcinoma cells engineered for inducible expression of c-Src. The presence of compound (8) resulted in the increased activity of the induced c-Src implicating that (8) acts as a c-Src activator in vivo. These observations are supported by computer modelling studies which suggest that the aldehyde group of (8) may covalently bind to a lysine residue in the SH2-kinase linker region situated in the proximity of the SH3 domain, which could promote a conformational change resulting in increased Src activity.

MeSH terms

  • Benzaldehydes / chemistry*
  • Carcinoma / drug therapy
  • Carcinoma / enzymology*
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / enzymology*
  • Computer Simulation
  • Enzyme Activation / drug effects
  • Enzyme Activators / chemical synthesis
  • Enzyme Activators / chemistry
  • Enzyme Activators / pharmacology
  • Fluorine*
  • Humans
  • Models, Biological
  • Molecular Structure
  • Protein Conformation
  • o-Phthalaldehyde / analogs & derivatives*
  • o-Phthalaldehyde / chemical synthesis
  • o-Phthalaldehyde / chemistry
  • o-Phthalaldehyde / pharmacology
  • src-Family Kinases / chemistry
  • src-Family Kinases / drug effects*
  • src-Family Kinases / metabolism*

Substances

  • 2,4-difluoro-5-(1-methoxy-2-methylpropyl)isophthalaldehyde
  • Benzaldehydes
  • Enzyme Activators
  • UCS15A
  • Fluorine
  • o-Phthalaldehyde
  • src-Family Kinases