title: Development of a highly selective c-Src kinase inhibitor.
abstract: Generating highly selective probes to interrogate protein kinase function in biological studies remains a challenge, and new strategies are required. Herein, we describe the development of the first highly selective and cell-permeable inhibitor of c-Src, a key signaling kinase in cancer. Our strategy involves extension of traditional inhibitor design by appending functionality proposed to interact with the phosphate-binding loop of c-Src. Using our selective inhibitor, we demonstrate that selective inhibition is significantly more efficacious than pan-kinase inhibition in slowing the growth of cancer cells. We also show that inhibition of c-Abl kinase, an off-target of most c-Src inhibitors, promotes oncogenic cell growth.
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109, USA.
authors.forename: Kristoffer R
authors.initials: KR
authors.lastname: Brandvold
authors.forename: Michael E
authors.initials: ME
authors.lastname: Steffey
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; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007700:Kinetics; D051379:Mice; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010710:Phosphates / Q000737:chemistry; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015398:Signal Transduction; D019061:src-Family Kinases
chemical_list: D000970:Antineoplastic Agents; D010710:Phosphates; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human