Inhibition of lymphoid tyrosine phosphatase by benzofuran salicylic acids
| Autor: | Deborah H. Smith, Alison Rinderspacher, Shi Xian Deng, Dusica Vidovic, Torkel Vang, Stephan C. Schürer, Tomas Mustelin, Robert C. Rickert, Yidong Liu, Donald W. Landry, Yuli Xie, Gangli Gong, Wallace Liu, Lutz Tautz, Caty Chung, Shuangding Wu |
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| Rok vydání: | 2010 |
| Předmět: |
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Molecular T-Lymphocytes Phosphatase Receptors Antigen T-Cell Protein tyrosine phosphatase medicine.disease_cause Jurkat cells Article Autoimmunity PTPN22 Small Molecule Libraries Jurkat Cells Structure-Activity Relationship Antigen Drug Discovery medicine Humans Tyrosine Benzofurans NFATC Transcription Factors Chemistry T-cell receptor Protein Tyrosine Phosphatase Non-Receptor Type 22 Molecular biology Recombinant Proteins Salicylates Transcription Factor AP-1 Biochemistry Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 54(2) |
| ISSN: | 1520-4804 |
| Popis: | The lymphoid tyrosine phosphatase (Lyp, PTPN22) is a critical negative regulator of T cell antigen receptor (TCR) signaling. A single-nucleotide polymorphism (SNP) in the ptpn22 gene correlates with the incidence of various autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Since the disease-associated allele is a more potent inhibitor of TCR signaling, specific Lyp inhibitors may become valuable in treating autoimmunity. Using a structure-based approach, we synthesized a library of 34 compounds that inhibited Lyp with IC(50) values between 0.27 and 6.2 μM. A reporter assay was employed to screen for compounds that enhanced TCR signaling in cells, and several inhibitors displayed a dose-dependent, activating effect. Subsequent probing for Lyp's direct physiological targets by immunoblot analysis confirmed the ability of the compounds to inhibit Lyp in T cells. Selectivity profiling against closely related tyrosine phosphatases and in silico docking studies with the crystal structure of Lyp yielded valuable information for the design of Lyp-specific compounds. |
| Databáze: | OpenAIRE |
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