Discovery of potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70
| Autor: | Selvi Pradeepan, Chi B. Vu, Tomi K. Sawyer, Shelia Violette, van Schravendijk Mr, Ian A. MacNeil, Catherine Bartlett, Mary K. Ram, Botfield Mc, Charles J. Eyermann, Berkley A. Lynch, Taylor Merry, Evelyn G. Corpuz, Regine S. Bohacek |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Models
Molecular Enzyme Precursors Oxadiazoles ZAP-70 Protein-Tyrosine Kinase biology Tetrapeptide Stereochemistry Chemistry Intracellular Signaling Peptides and Proteins Syk Protein-Tyrosine Kinases SH2 domain Receptor tyrosine kinase SH3 domain src Homology Domains Structure-Activity Relationship Biochemistry Drug Discovery biology.protein Molecular Medicine Syk Kinase GRB2 Enzyme Inhibitors Tyrosine kinase Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Journal of medicinal chemistry. 42(20) |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|