Exquisitely specific bisubstrate inhibitors of c-Src kinase

ACS Chemical Biology
Kristoffer R BrandvoldMatthew B Soellner

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.

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Citations

Feb 24, 2016·Future Medicinal Chemistry·Sean MaddoxJeffrey L Gustafson
Jun 9, 2016·Bioconjugate Chemistry·Taylor K Johnson, Matthew B Soellner
Jun 16, 2016·Chembiochem : a European Journal of Chemical Biology·Aaron R Van DykeVictoria Jedson
Mar 18, 2021·European Journal of Medicinal Chemistry·Seungbeom LeeHwayoung Yun

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