1. Difluoro analogue of UCS15A triggers activation of exogenously expressed c-Src in HCT 116 human colorectal carcinoma cells
- Author
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Arkadiusz Welman, Sally Freeman, Christopher Cawthorne, Caroline Dive, Richard A. Bryce, Jane Barraclough, and Noor Atatreh
- Subjects
Conformational change ,Protein Conformation ,Enzyme Activators ,Biology ,Models, Biological ,SH3 domain ,Cell Line, Tumor ,Drug Discovery ,Humans ,Computer Simulation ,Kinase activity ,Pharmacology ,Src homology domain ,Molecular Structure ,Activator (genetics) ,Effector ,Carcinoma ,General Medicine ,Fluorine ,Molecular biology ,Enzyme Activation ,src-Family Kinases ,Benzaldehydes ,Colorectal Neoplasms ,Tyrosine kinase ,o-Phthalaldehyde ,Proto-oncogene tyrosine-protein kinase Src - 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. more...
- Published
- 2007