Difluoro analogue of UCS15A triggers activation of exogenously expressed c-Src in HCT 116 human colorectal carcinoma cells.
Bryce, Richard A
AffiliationSchool of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PT, UK.
MetadataShow full item record
AbstractUCS 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.
CitationDifluoro analogue of UCS15A triggers activation of exogenously expressed c-Src in HCT 116 human colorectal carcinoma cells. 2007, 22 (5):638-46 J Enzyme Inhib Med Chem
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
- UCS15A, a novel small molecule, SH3 domain-mediated protein-protein interaction blocking drug.
- Authors: Oneyama C, Nakano H, Sharma SV
- Issue date: 2002 Mar 27
- UCS15A, a non-kinase inhibitor of Src signal transduction.
- Authors: Sharma SV, Oneyama C, Yamashita Y, Nakano H, Sugawara K, Hamada M, Kosaka N, Tamaoki T
- Issue date: 2001 Apr 19
- SH3-dependent stimulation of Src-family kinase autophosphorylation without tail release from the SH2 domain in vivo.
- Authors: Lerner EC, Smithgall TE
- Issue date: 2002 May
- Novel mechanism of regulation of the non-receptor protein tyrosine kinase Csk: insights from NMR mapping studies and site-directed mutagenesis.
- Authors: Shekhtman A, Ghose R, Wang D, Cole PA, Cowburn D
- Issue date: 2001 Nov 16
- Roles of the SH2 and SH3 domains in the regulation of neuronal Src kinase functions.
- Authors: Groveman BR, Xue S, Marin V, Xu J, Ali MK, Bienkiewicz EA, Yu XM
- Issue date: 2011 Feb