title: Exquisitely specific bisubstrate inhibitors of c-Src kinase.
abstract: 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.
authors: †Department of Medicinal Chemistry and ‡Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States.
authors: Kristoffer R
authors: KR
authors: Brandvold
authors: †Department of Medicinal Chemistry and ‡Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States.
authors: Shana M
authors: SM
authors: Santos
authors: †Department of Medicinal Chemistry and ‡Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States.
authors: Meghan E
authors: ME
authors: Breen
authors: †Department of Medicinal Chemistry and ‡Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States.
authors: Eric J
authors: EJ
authors: Lachacz
authors: †Department of Medicinal Chemistry and ‡Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States.
authors: Michael E
authors: ME
authors: Steffey
authors: †Department of Medicinal Chemistry and ‡Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States.
authors: Matthew B
authors: MB
authors: Soellner
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry*; D001667:Binding, Competitive; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D010455:Peptides; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human