Breen Meghan E, Steffey Michael E, Lachacz Eric J, Kwarcinski Frank E, Fox Christel C, Soellner Matthew B
Departments of Medicinal Chemistry and Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109 (USA).
Angew Chem Int Ed Engl. 2014 Jul 1;53(27):7010-3. doi: 10.1002/anie.201311096. Epub 2014 May 2.
Substrate-competitive 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 small-molecule substrates for any protein kinase were discovered, as well as the first substrate-competitive inhibitors of c-Src with activity in both biochemical and cellular assays. Characterization of the lead inhibitor demonstrates that substrate-competitive kinase inhibitors possess unique properties, including cellular efficacy that matches biochemical potency and synergy with ATP-competitive inhibitors.
底物竞争性激酶抑制剂是一类很有前景的激酶抑制剂,然而,目前尚无选择性鉴定这类抑制剂的方法。底物活性筛选应用于酪氨酸激酶。通过使用这种方法,发现了任何蛋白激酶的首个小分子底物,以及c-Src在生化和细胞试验中均具有活性的首个底物竞争性抑制剂。先导抑制剂的特性表明,底物竞争性激酶抑制剂具有独特的性质,包括与生化效力相匹配的细胞功效以及与ATP竞争性抑制剂的协同作用。