title: Structure-based design and solid-phase parallel synthesis of phosphorylated nonpeptides to explore hydrophobic binding at the Src SH2 domain.
abstract: Using a novel, solid-phase parallel synthetic route and a computational docking program, a series of phosphorylated nonpeptides were generated to determine their structure-activity relationships (SAR) for binding at the SH2 domain of pp60src (Src). A functionalized benzoic acid intermediate was attached to solid support via Rink amide linkage, which upon acid cleavage generated the desired benzamide template-based nonpeptides in a facile manner. Compounds were synthesized using a combination of solid- and solution-phase techniques. Purification using reversed-phase, semipreparative HPLC allowed for quantitative SAR studies. Specifically, this work focused on functional group modifications, in a parallel fashion, designed to explore hydrophobic binding at the pY+3 pocket of the Src SH2 domain.
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139-4234, USA. chet.metcalf@ariad.com
authors.forename: C A
authors.initials: CA
authors.lastname: Metcalf
authors.forename: C J
authors.initials: CJ
authors.lastname: Eyermann
authors.forename: R S
authors.initials: RS
authors.lastname: Bohacek
authors.forename: C A
authors.initials: CA
authors.lastname: Haraldson
authors.forename: V M
authors.initials: VM
authors.lastname: Varkhedkar
authors.forename: B A
authors.initials: BA
authors.lastname: Lynch
authors.forename: C
authors.initials: C
authors.lastname: Bartlett
authors.forename: S M
authors.initials: SM
authors.lastname: Violette
authors.forename: T K
authors.initials: TK
authors.lastname: Sawyer
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry*; D013329:Structure-Activity Relationship; D018909:src Homology Domains
chemical_list: D001549:Benzamides; D016392:Proto-Oncogene Proteins pp60(c-src)