title: Design, synthesis, and cocrystal structure of a nonpeptide Src SH2 domain ligand.
abstract: The specific association of an SH2 domain with a phosphotyrosine (pTyr)-containing sequence of another protein precipitates a cascade of intracellular molecular interactions (signals) which effect a wide range of intracellular processes. The nonreceptor tyrosine kinase Src, which has been associated with breast cancer and osteoporosis, contains an SH2 domain. Inhibition of Src SH2-phosphoprotein interactions by small molecules will aid biological proof-of-concept studies which may lead to the development of novel therapeutic agents. Structure-based design efforts have focused on reducing the size and charge of Src SH2 ligands while increasing their ability to penetrate cells and reach the intracellular Src SH2 domain target. In this report we describe the synthesis, binding affinity, and Src SH2 cocrystal structure of a small, novel, nonpeptide, urea-containing SH2 domain ligand.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Plummer
authors.forename: D R
authors.initials: DR
authors.lastname: Holland
authors.forename: A
authors.initials: A
authors.lastname: Shahripour
authors.forename: E A
authors.initials: EA
authors.lastname: Lunney
authors.forename: J H
authors.initials: JH
authors.lastname: Fergus
authors.forename: J S
authors.initials: JS
authors.lastname: Marks
authors.forename: P
authors.initials: P
authors.lastname: McConnell
authors.forename: W T
authors.initials: WT
authors.lastname: Mueller
authors.forename: T K
authors.initials: TK
authors.lastname: Sawyer
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D008024:Ligands; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D018909:src Homology Domains / Q000502:physiology*
chemical_list: D004151:Dipeptides; D008024:Ligands; D009842:Oligopeptides; D014508:Urea