Discovery of potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70.
J Med Chem
; 42(20): 4088-98, 1999 Oct 07.
Article
en En
| MEDLINE
| ID: mdl-10514279
ABSTRACT
A series of 1,2,4-oxadiazole analogues has been shown to be potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70, a potential therapeutic target for immune suppression. These compounds typically are 200-400-fold more potent than the native, monophosphorylated tetrapeptide sequences. When compared with the high-affinity zeta-1-ITAM peptide (Ac-NQL-pYNELNLGRREE-pYDVLD-NH(2), wherein pY refers to phosphotyrosine) some of the best 1,2, 4-oxadiazole analogues are approximately 1 order of magnitude less active. This series of compounds displays an unprecedented level of selectivity over the closely related tyrosine kinase Syk, as well as other SH2-containing proteins such as Src and Grb2. Gel shift studies using a protein construct consisting only of C-terminal ZAP-70 SH2 demonstrate that these compounds can effectively engage this particular SH2 domain.
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Base de datos:
MEDLINE
Asunto principal:
Oxadiazoles
/
Proteínas Tirosina Quinasas
/
Dominios Homologos src
/
Inhibidores Enzimáticos
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1999
Tipo del documento:
Article
País de afiliación:
Estados Unidos