Discovery of a novel submicromolar inhibitor of the lymphoid specific tyrosine phosphatase

We have screened a small library of thiuram disulfides for inhibition of lymphoid tyrosine phosphatase (LYP) activity. The parent thiuram disulfide, disulfiram, inhibited LYP activity in vitro and in Jurkat T cells whereas diethyldithiocarbamate failed to inihibit LYP at the concentrations tested. Compound 13, an N-(2-thioxothiazolidin-4-one) analog, was the most potent LYP inhibitor in this series, with an IC50 of 3 μM. Compound 13 was found to inhibit LYP pseudo-irreversibly, as evident by the time-dependence of inhibition with a Ki of 1.1 μM and a kinact of 0.004 s−1. The inhibition of LYP by compound 13 could not be reversed significantly by incubation with glutathione or by prolonged dialysis, but could be partially reversed by incubation with dithiothreitol. Compound 13 also inhibited LYP activity in Jurkat T cells.

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“…This is not surprising as a class of thiazolidine-2,4-diones have previously been reported to inhibit LYP at submicromolar concentrations. [31] …”

Section: Resultsmentioning

confidence: 99%

Thiuram Disulfides as Pseudo‐irreversible Inhibitors of Lymphoid Tyrosine Phosphatase

et al. 2013

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“…As PTPN22 is implicated in many prevalent autoimmune diseases (and perhaps even in transplant rejection), an anti-LYP drug that could reverse the negative effects of the W620 variant on TCR signaling would be of broad value for the treatment of multiple human conditions [23,24].…”

Section: Discussionmentioning

confidence: 99%

The role of PTPN22 gene polymorphism in childhood immune thrombocytopenic purpura

Anis

Ghany²,

Mostafa³

et al. 2011

Blood Coagulation &Amp; Fibrinolysis

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Immune thrombocytopenia is an autoimmune disorder characterized by antibody-mediated platelet destruction. A protein tyrosine phosphatase (PTPN22) present in lymphocytes is an important negative regulator of signal transduction for the T-cell receptor-MHC complex and has been associated with autoimmune disorders that produce autoantibodies. The present study investigated the frequency of the 1858C>T single-nucleotide polymorphism (SNP) in the PTPN22 gene in idiopathic thrombocytopenic purpura (ITP) patients. This case series study included 50 children with ITP, 24 acute and 26 chronic cases, and 50 normal children as a control group. All were subjected to clinical history and laboratory investigations including complete blood count, genotyping of PTPN22 1858C/T SNP by polymerase chain reaction-restriction fragment length polymorphism and platelet antibodies using platelets suspension immunofluorescence test for the cases. Thirteen patients (26%) were positive for the PTPN22 1858C>T SNP. Three patients were homozygous for the mutation and 10 were heterozygous. Comparison of the 26% of the ITP patients who were positive for the PTPN22 1858C>T mutation with the 6% positive in the control group yielded a P value of 0.006. Antiplatelet antibodies were detected in five patients (20.8%) with acute ITP and in three patients (11.5%) with chronic ITP; no significant association between the presence of PTPN22 1858C>T mutation and the presence of antiplatelet antibodies was detected. The prevalence of PTPN22 gene mutation was higher in ITP patients, thus it may be considered as a genetic risk factor in the development of ITP in Egyptian children.

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“…These compounds were further optimized by a fragment-based approach with a total of 25 thiazolidinedione analogs being synthesized and tested. Seventeen of them showed potency toward LYP (IC 50 \ 44 lM) [22]. Their structures and activities (IC 50 in lM units) are given in Table 1.…”

Section: Small Molecule Ligandsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Vidović

Xie

Rinderspacher

et al. 2011

J Comput Aided Mol Des

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The lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene, has recently been identified as a promising drug target for human autoimmunity diseases. Like the majority of protein-tyrosine phosphatases LYP can adopt two functionally distinct forms determined by the conformation of the WPD-loop. The WPD-loop plays an important role in the catalytic dephosphorylation by protein-tyrosine phosphatases. Here we investigate the binding modes of two chemotypes of small molecule LYP inhibitors with respect to both protein conformations using computational modeling. To evaluate binding in the active form, we built a LYP protein structure model of high quality. Our results suggest that the two different compound classes investigated, bind to different conformations of the LYP phosphatase domain. Binding to the closed form is facilitated by an interaction with Asp195 in the WPD-loop, presumably stabilizing the active conformation. The analysis presented here is relevant for the design of inhibitors that specifically target either the closed or the open conformation of LYP in order to achieve better selectivity over phosphatases with similar binding sites.

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Discovery of a novel submicromolar inhibitor of the lymphoid specific tyrosine phosphatase

Cited by 36 publications

References 5 publications

Thiuram Disulfides as Pseudo‐irreversible Inhibitors of Lymphoid Tyrosine Phosphatase

Thiuram Disulfides as Pseudo‐irreversible Inhibitors of Lymphoid Tyrosine Phosphatase

The role of PTPN22 gene polymorphism in childhood immune thrombocytopenic purpura

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

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