Document Report Card

ID: ALA1132280

Journal: J Med Chem

Title: Discovery of potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70.

Authors: Vu CB, Corpuz EG, Merry TJ, Pradeepan SG, Bartlett C, Bohacek RS, Botfield MC, Eyermann CJ, Lynch BA, MacNeil IA, Ram MK, van Schravendijk MR, Violette S, Sawyer TK.

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.

CiteXplore: 10514279

DOI: 10.1021/jm990229t