Difluoro analogue of UCS15A triggers activation of exogenously expressed c-Src in HCT 116 human colorectal carcinoma cells.
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.
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PT, UK.
Noor
N
Atatreh
Jane
J
Barraclough
Arkadiusz
A
Welman
Christopher
C
Cawthorne
Richard A
RA
Bryce
Caroline
C
Dive
Sally
S
Freeman
D001547:Benzaldehydes / Q000737:chemistry*; D002277:Carcinoma / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D003198:Computer Simulation; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005461:Fluorine; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D011487:Protein Conformation; D009764:o-Phthalaldehyde / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019061:src-Family Kinases / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*
C527599:2,4-difluoro-5-(1-methoxy-2-methylpropyl)isophthalaldehyde; D001547:Benzaldehydes; D020536:Enzyme Activators; C426883:UCS15A; D005461:Fluorine; D009764:o-Phthalaldehyde; D019061:src-Family Kinases