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

A series of 1,2,4-oxadiazole analogues has been shown to be potent and sele ctive 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. Whe n compared with the high-affinity xi-1-ITAM peptide (Ac-NQL-pYNELNLGRREE-pY DVLD-NH2, wherein pY refers to phosphotyrosine) some of the best 1,2,4-oxad iazole analogues are approximately 1 order of magnitude less active. This s eries of compounds displays an unprecedented level of selectivity over the closely related tyrosine kinase Syk, as well as other SH2-containing protei ns such as Src and Grb2. Gel shift studies using a protein construct consis ting only of C-terminal ZAP-70 SH2 demonstrate that these compounds can eff ectively engage this particular SH2 domain.