Brandvold Kristoffer R, Santos Shana M, Breen Meghan E, Lachacz Eric J, Steffey Michael E, Soellner Matthew B
†Department of Medicinal Chemistry and ‡Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States.
ACS Chem Biol. 2015 Jun 19;10(6):1387-91. doi: 10.1021/cb501048b. Epub 2015 Mar 31.
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.
我们已经开发出一种用于双底物抑制蛋白激酶的模块化方法。我们将该方法应用于c-Src，并鉴定出针对此靶点的一种高选择性双底物抑制剂。我们的方法产生了迄今为止最具选择性的c-Src抑制剂，并且使双底物抑制剂具有细胞渗透性的方法为研究c-Src信号传导提供了一个非常有价值的工具。此外，我们已将我们的双底物抑制剂应用于开发一种新型筛选方法，以鉴定c-Src的非ATP竞争性抑制剂。使用这种方法，我们发现了迄今为止报道的最有效的非ATP竞争性抑制剂。我们的方法设计得具有通用性，可能适用于受我们研究中使用的混杂ATP竞争性片段抑制的其他激酶。
