Substrate Activity Screening for Kinases: Discovery of Small Molecule Substrate-Competitive c-Src Inhibitors

摘要

Substrate-competitive kinase inhibitors represent a promising class of kinase inhibitors, however, there is no methodology to selectively identify this type of inhibitor. Herein, we report the application of substrate activity screening to tyrosine kinases. Using this methodology, we have discovered the first small molecule substrates for any protein kinase and the first substrate-competitive inhibitors of c-Src with activity in both biochemical and cellular assays. Characterization of our lead inhibitor demonstrates that substrate-competitive kinase inhibitors possess unique properties, including cellular efficacy that matches biochemical potency and synergy with ATP-competitive inhibitors.