title: Inhibition of lymphoid tyrosine phosphatase by benzofuran salicylic acids.
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.
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Torkel
authors.initials: T
authors.lastname: Vang
authors.forename: Yuli
authors.initials: Y
authors.lastname: Xie
authors.forename: Wallace H
authors.initials: WH
authors.lastname: Liu
authors.forename: Dusica
authors.initials: D
authors.lastname: Vidović
authors.forename: Yidong
authors.initials: Y
authors.lastname: Liu
authors.forename: Shuangding
authors.initials: S
authors.lastname: Wu
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Smith
authors.forename: Alison
authors.initials: A
authors.lastname: Rinderspacher
authors.forename: Caty
authors.initials: C
authors.lastname: Chung
authors.forename: Gangli
authors.initials: G
authors.lastname: Gong
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
authors.forename: Donald W
authors.initials: DW
authors.lastname: Landry
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rickert
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Schürer
authors.forename: Shi-Xian
authors.initials: SX
authors.lastname: Deng
authors.forename: Lutz
authors.initials: L
authors.lastname: Tautz
mesh_terms: D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D008958:Models, Molecular; D050778:NFATC Transcription Factors / Q000378:metabolism; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D012459:Salicylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D001572:Benzofurans; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D012459:Salicylates; D054852:Small Molecule Libraries; D018808:Transcription Factor AP-1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22