Ligands for the Tyrosine Kinase p56lck SH2 Domain: Discovery of Potent Dipeptide Derivatives with Monocharged, Nonhydrolyzable Phosphate Replacements
| Autor: | Jean Rancourt, Kirrane Thomas M, Rajiv Sharma, Martin Poirier, John R. Proudfoot, Susan Lukas, Montse Llinas-Brunet, Usha R. Patel, Dominik Wernic, Alisa K. Kabcenell, Pierre L. Beaulieu, Neil Moss, Scott Jakes, Vida Gorys, Jean Gauthier, Mario G. Cardozo, Liang Tong, Eugene R. Hickey, Dale R. Cameron, Jean-Marie Ferland, Raj Betageri, Richard H. Ingraham, James Gillard, Ghiro Elise |
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| Rok vydání: | 1999 |
| Předmět: |
Models
Molecular chemistry.chemical_classification Dipeptide Stereochemistry Peptide Dipeptides Crystallography X-Ray Ligands Ligand (biochemistry) SH2 domain src Homology Domains Structure-Activity Relationship chemistry.chemical_compound chemistry Lymphocyte Specific Protein Tyrosine Kinase p56(lck) Drug Discovery Molecular Medicine Moiety Structure–activity relationship Phosphorylation Tyrosine kinase Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 42:1757-1766 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm980676t |
| Popis: | p56lck is a member of the src family of tyrosine kinases. Through modular binding units called SH2 domains, p56lck promotes phosphotyrosine-dependent protein-protein interactions and plays a critical role in signal transduction events that lead to T-cell activation. Starting from the phosphorylated dipeptide (2), a high-affinity ligand for the p56lck SH2 domain, we have designed novel dipeptides that contain monocharged, nonhydrolyzable phosphate group replacements and bind to the protein with KD's in the low micromolar range. Replacement of the phosphate group in phosphotyrosine-containing sequences by a (R/S)-hydroxyacetic (compound 8) or an oxamic acid (compound 10) moiety leads to hydrolytically stable, monocharged ligands, with 83- and 233-fold decreases in potency, respectively. This loss in binding affinity can be partially compensated for by incorporating large lipophilic groups at the inhibitor N-terminus. These groups provide up to 13-fold increases in potency depending on the nature of the phosphate replacement. The discovery of potent (2-3 microM), hydrolytically stable dipeptide derivatives, bearing only two charges at physiological pH, represents a significant step toward the discovery of compounds with cellular activity and the development of novel therapeutics for conditions associated with undesired T-cell proliferation. |
| Databáze: | OpenAIRE |
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