Inhibition of Lymphoid Tyrosine Phosphatase by Benzofuran Salicylic Acids

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• 作者：Torkel Vang ; Yuli Xie ; Wallace H. Liu ; Dus虒ica Vidovic虂 ; Yidong Liu ; Shuangding Wu ; Deborah H. Smith ; Alison Rinderspacher ; Caty Chung ; Gangli Gong ; Tomas Mustelin ; Donald W. Landry ; Robert C. Rickert ; Stephan C. Schu虉rer ; Shi-Xian Deng ; Lutz Tautz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：January 27, 2011
• 年：2011
• 卷：54
• 期：2
• 页码：562-571
• 全文大小：1063K
• 年卷期：v.54,no.2(January 27, 2011)
• ISSN：1520-4804

文摘

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 IC₅₀ values between 0.27 and 6.2 渭M. 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鈥檚 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.