Potent reversible inhibitors of the protein tyrosine phosphatase CD45
| Autor: | Gary Steelman, Chapdelaine Marc, Katharine S. Knappenberger, Rebecca Urbanek, Linda A. Sygowski, Chris Allan Veale, Suzanne J. Suchard |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Cellular immunity
T-Lymphocytes Protein tyrosine phosphatase In Vitro Techniques Nitrophenols Structure-Activity Relationship Organophosphorus Compounds Drug Discovery Humans Enzyme Inhibitors Cells Cultured chemistry.chemical_classification Protein Tyrosine Phosphatase Non-Receptor Type 1 biology Chemistry Hydrolysis Phenanthrenes Transmembrane protein Enzyme Biochemistry Enzyme inhibitor biology.protein Molecular Medicine Phosphorylation Leukocyte Common Antigens Signal transduction Pharmacophore Protein Tyrosine Phosphatases Oligopeptides Cell Division Naphthoquinones |
| Zdroj: | Journal of medicinal chemistry. 44(11) |
| ISSN: | 0022-2623 |
| Popis: | The cytosolic portion of CD45, a major transmembrane glycoprotein found on nucleated hematopoietic cells, contains protein tyrosine phosphatase activity and is critical for T-cell receptor-mediated T-cell activation. CD45 inhibitors could have utility in the treatment of autoimmune disorders and organ graft rejection. A number of 9,10-phenanthrenediones were identified that reversibly inhibited CD45-mediated p-nitrophenyl phosphate (pNPP) hydrolysis. Chemistry efforts around the 9,10-phenanthrenedione core led to the most potent inhibitors known to date. In a functional assay, the compounds were also potent inhibitors of T-cell receptor-mediated proliferation, with activities in the low micromolar range paralleling their enzyme inhibition. It was also discovered that the nature of modification to the phenanthrenedione pharmacophore could affect selectivity for CD45 over PTP1B (protein tyrosine phosphatase 1B) or vice versa. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|