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Exquisitely specific bisubstrate inhibitors of c-Src kinase.

ABSTRACT: 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.

SUBMITTER: Brandvold KR

PROVIDER: S-EPMC4578647 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Exquisitely specific bisubstrate inhibitors of c-Src kinase.

Brandvold Kristoffer R KR Santos Shana M SM Breen Meghan E ME Lachacz Eric J EJ Steffey Michael E ME Soellner Matthew B MB

ACS chemical biology 20150331 6

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 identif ...[more]

PMID: 25793938

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