Discovery of highly potent Src SH2 binders: structure-activity studies and X-ray structures.
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).
Deprez
Pierre
P
Aventis Pharma, Paris Research Center, Medicinal Chemistry, 102 route de Noisy, 93235 Cedex, Romainville, France. pierre.deprez@aventis.com
Baholet
Isabelle
I
Burlet
Stéphane
S
Lange
Gudrun
G
Amengual
Remi
R
Schoot
Bernard
B
Vermond
Annie
A
Mandine
Eliane
E
Lesuisse
Dominique
D
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
D001565:Benzoates; D009943:Organophosphorus Compounds; C466036:RU 79181; C466035:RU 81843; D019000:Phosphotyrosine; D002209:Caprolactam