title: Irreversible inhibitors of c-Src kinase that target a nonconserved cysteine.
abstract: We have developed the first irreversible inhibitors of wild-type c-Src kinase. We demonstrate that our irreversible inhibitors display improved potency and selectivity relative to that of their reversible counterparts. Our strategy involves modifying a promiscuous kinase inhibitor with an electrophile to generate covalent inhibitors of c-Src. We applied this methodology to two inhibitor scaffolds that exhibit increased cellular efficacy when rendered irreversible. In addition, we have demonstrated the utility of irreversible inhibitors in studying the conformation of an important loop in kinases that can control inhibitor selectivity and cause drug resistance. Together, we have developed a general and robust framework for generating selective irreversible inhibitors from reversible, promiscuous inhibitor scaffolds.
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States.
authors.forename: Frank E
authors.initials: FE
authors.lastname: Kwarcinski
authors.forename: Christel C
authors.initials: CC
authors.lastname: Fox
authors.forename: Michael E
authors.initials: ME
authors.lastname: Steffey
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Soellner
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human