title: Discovery of highly potent Src SH2 binders: structure-activity studies and X-ray structures.
abstract: Optimization of the hydrophobic moiety of caprolactam/thiazepinone based compounds led to the identification of potent Src SH2 binders in two different series incorporating a phosphotyrosine group (RU 81843) or a phosphobenzoic group (RU 79181). The X-ray co-structures with the Src SH2 domain revealed different binding modes for RU 81843 and RU 79181, and an excellent fit between RU81843 and the Src SH2 protein thus explaining its high potency (9 nM, 15-fold more potent than pYEEI reference peptide).
authors.affiliation: Aventis Pharma, Paris Research Center, Medicinal Chemistry, 102 route de Noisy, 93235 Cedex, Romainville, France. pierre.deprez@aventis.com
authors.forename: Pierre
authors.initials: P
authors.lastname: Deprez
authors.forename: Isabelle
authors.initials: I
authors.lastname: Baholet
authors.forename: Stéphane
authors.initials: S
authors.lastname: Burlet
authors.forename: Gudrun
authors.initials: G
authors.lastname: Lange
authors.forename: Remi
authors.initials: R
authors.lastname: Amengual
authors.forename: Bernard
authors.initials: B
authors.lastname: Schoot
authors.forename: Annie
authors.initials: A
authors.lastname: Vermond
authors.forename: Eliane
authors.initials: E
authors.lastname: Mandine
authors.forename: Dominique
authors.initials: D
authors.lastname: Lesuisse
mesh_terms: D001565:Benzoates / Q000737:chemistry / Q000378:metabolism*; D002209:Caprolactam / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism*; D019000:Phosphotyrosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction; D018909:src Homology Domains
chemical_list: D001565:Benzoates; D009943:Organophosphorus Compounds; C466036:RU 79181; C466035:RU 81843; D019000:Phosphotyrosine; D002209:Caprolactam