Exquisitely Specific Bisubstrate Inhibitors of c-Src Kinase
Brandvold, K.R.; Santos, S.M.; Breen, M.E.; Lachacz, E.J.; Steffey, M.E.; Soellner, M.B. Exquisitely Specific Bisubstrate Inhibitors of c-Src Kinase. ACS Chem. Biol. 2015, 10, 6, 1387-1391.
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.
ACS chemical biology