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.

Efficient Syntheses of 1,2,3-Triazoloamide Derivatives Using Solid- and Solution-Phase Synthetic Approaches

“…Molecules 2015, 20, page-page 2 [16], as protein tyrosine phosphatase (PTPs) inhibitors [17], as lymphoid tyrosin phosphatase (Lyp, PTPN22) inhibitors [18], and as glucokinase (GK) acitvators [19].…”

“…Various α-1,2,3-triazoloamide derivatives have been shown to exhibit a wide range of biological activities [11][12][13][14][15][16][17][18][19]. In recent examples, α-1,2,3-triazoloamide related compounds have been developed and studied as tropomysin receptor kinase A (TrkA) inhibitors [11], as inhibitors of Mycobacterium tuberculosis [12], as phosphodiesterase 4B (PDE4B) inhibitor for anticancer agents [13], as quorum …”

Medicinal Chemistry in the Context of the Human Genome

“…The phosphatases share a high homology at the catalytic center and therefore structural information is crucial for the design of selective ligands. Recently, more selective inhibitors have been identified for PTP1B, hematopoietic protein tyrosine phosphatase (HePTP), lymphoid PTP (LYP), and Src homology 2 domain-containing PTP (SHP2), all of which are bidentate and target the active center with a carboxylic acid moiety and an adjacent binding pocket with a lipophilic (aromatic) moiety [55][56][57][58][59]. Structures of the catalytic domains from all of the PTP subfamilies have been published by the SGC [60].…”

Distinct functional and conformational states of the human lymphoid tyrosine phosphatase catalytic domain can be targeted by choice of the inhibitor chemotype

“…A 34 member library of 6-hydroxybenzofuran-5-carboxylic acid-based ligands (I-C11 analogs) was synthesized and subsequently evaluated in a LYP enzyme activity assay [23]. Interestingly, most of the I-C11 analogs showed higher potency than I-C11 itself.…”

“…Active series were identified and further optimized in a medicinal chemistry program. Two main chemotypes emerged, a series of thiazolidinedionederived [22] and a series of 6-hydroxybenzofuran-5-carboxylic acid [23] inhibitors. Here we employed structurebased computational modeling to evaluate and analyze the binding modes of these two different classes of compounds.…”