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Substrate Activity Screening with Kinases: Discovery of Small‐Molecule Substrate‐Competitive c‐Src Inhibitors
Author(s) -
Breen Meghan E.,
Steffey Michael E.,
Lachacz Eric J.,
Kwarcinski Frank E.,
Fox Christel C.,
Soellner Matthew B.
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201311096
Subject(s) - kinase , substrate (aquarium) , small molecule , biochemistry , tyrosine kinase , proto oncogene tyrosine protein kinase src , chemistry , non competitive inhibition , sh3 domain , enzyme , biology , signal transduction , ecology
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.