Inhibition of lymphoid tyrosine phosphatase by benzofuran salicylic acids

Torkel Vang, Yuli Xie, Wallace H. Liu, Dušica Vidović, Yidong Liu, Shuangding Wu, Deborah H. Smith, Alison Rinderspacher, Caty Chung, Gangli Gong, Tomas Mustelin, Donald W. Landry, Robert C. Rickert, Stephan C. Schürer, Shi Xian Deng, Lutz Tautz

Research output: Contribution to journalArticle

32 Scopus citations

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 IC50 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 Lyps 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.

Original languageEnglish (US)
Pages (from-to)562-571
Number of pages10
JournalJournal of Medicinal Chemistry
Volume54
Issue number2
DOIs
Publication statusPublished - Jan 27 2011

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Vang, T., Xie, Y., Liu, W. H., Vidović, D., Liu, Y., Wu, S., ... Tautz, L. (2011). Inhibition of lymphoid tyrosine phosphatase by benzofuran salicylic acids. Journal of Medicinal Chemistry, 54(2), 562-571. https://doi.org/10.1021/jm101004d