4 research outputs found
Substrate Activity Screening with Kinases: Discovery of SmallāMolecule SubstrateāCompetitive cāSrc Inhibitors
Substrateācompetitive kinase inhibitors represent a promising class of kinase inhibitors, however, there is no methodology to selectively identify this type of inhibitor. Substrate activity screening was applied to tyrosine kinases. By using this methodology, the first smallāmolecule substrates for any protein kinase were discovered, as well as the first substrateācompetitive inhibitors of cāSrc with activity in both biochemical and cellular assays. Characterization of the lead inhibitor demonstrates that substrateācompetitive kinase inhibitors possess unique properties, including cellular efficacy that matches biochemical potency and synergy with ATPācompetitive inhibitors. SASsy inhibitors : Smallāmolecule substrateācompetitive inhibitors of the tyrosine kinase cāSrc were discovered through the application of substrate activity screening (SAS). Characterization of the lead inhibitor demonstrates that substrateācompetitive kinase inhibitors possess unique properties, including cellular efficacy that matches biochemical potency and synergy with ATPācompetitive inhibitors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107499/1/7010_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/107499/2/anie_201311096_sm_miscellaneous_information.pd
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Exquisitely Specific Bisubstrate Inhibitors of cāSrc Kinase
We have developed a modular approach
to bisubstrate inhibition
of protein kinases. We apply our methodology to c-Src and identify
a highly selective bisubstrate inhibitor for this target. Our approach
has yielded the most selective c-Src inhibitor to date, and the methodology
to render the bisubstrate inhibitor cell-permeable provides a highly
valuable tool for the study of c-Src signaling. In addition, we have
applied our bisubstrate inhibitor to develop a novel screening methodology
to identify non-ATP-competitive inhibitors of c-Src. Using this methodology,
we have discovered the most potent non-ATP-competitive inhibitor reported
to date. Our methodology is designed to be general and could be applicable
to additional kinases inhibited by the promiscuous ATP-competitive
fragment used in our studies