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Inhibition of lymphoid tyrosine phosphatase by benzofuran salicylic acids.

Authors
  • Vang, Torkel
  • Xie, Yuli
  • Liu, Wallace H
  • Vidović, Dusica
  • Liu, Yidong
  • Wu, Shuangding
  • Smith, Deborah H
  • Rinderspacher, Alison
  • Chung, Caty
  • Gong, Gangli
  • Mustelin, Tomas
  • Landry, Donald W
  • Rickert, Robert C
  • Schürer, Stephan C
  • Deng, Shi-Xian
  • Tautz, Lutz
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Jan 27, 2011
Volume
54
Issue
2
Pages
562–571
Identifiers
DOI: 10.1021/jm101004d
PMID: 21190368
Source
Medline
License
Unknown

Abstract

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.

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