title: Substrate activity screening with kinases: discovery of small-molecule substrate-competitive c-Src inhibitors.
abstract: 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.
authors.affiliation: Departments of Medicinal Chemistry and Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109 (USA).
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Breen
authors.forename: Michael E
authors.initials: ME
authors.lastname: Steffey
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lachacz
authors.forename: Frank E
authors.initials: FE
authors.lastname: Kwarcinski
authors.forename: Christel C
authors.initials: CC
authors.lastname: Fox
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Soellner
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D013379:Substrate Specificity; D019061:src-Family Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human
keywords: drug discovery; inhibitors; kinases; medicinal chemistry; substrate activity screening