Allosteric Noncompetitive Small Molecule Selective Inhibitors of CD45 Tyrosine Phosphatase Suppress T-Cell Receptor Signals and Inflammation In Vivo

Perron, Michael D.; Chowdhury, Subrata; Aubry, Isabelle; Purisima, Enrico O.; Tremblay, Michel L.; Saragovi, H. Uri

doi:10.1124/mol.113.089847

Cited by 25 publications

(39 citation statements)

References 42 publications

(46 reference statements)

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“…Still, the specificity of this inhibitor could be an issue since most receptor tyrosine phosphatases possess a well-conserved wedge domain. An alternative approach is to use specific allosteric inhibitors [29] or, as shown here, antibodies targeted to the extracellular domain of RPTPs.…”

Section: Discussionmentioning

confidence: 99%

Identification of function-regulating antibodies targeting the receptor protein tyrosine phosphatase sigma ectodomain

Hardy

Aubry

et al. 2017

PLoS ONE

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Receptor tyrosine phosphatase sigma (RPTPσ) plays an important role in the regulation of axonal outgrowth and neural regeneration. Recent studies have identified two RPTPσ ligands, chondroitin sulfate proteoglycans (CSPGs) and heparan sulfate proteoglycans (HSPG), which can modulate RPTPσ activity by affecting its dimerization status. Here, we developed a split luciferase assay to monitor RPTPσ dimerization in living cells. Using this system, we demonstrate that heparin, an analog of heparan sulfate, induced the dimerization of RPTPσ, whereas chondroitin sulfate increased RPTPσ activity by inhibiting RPTPσ dimerization. Also, we generated several novel RPTPσ IgG monoclonal antibodies, to identify one that modulates its activity by inducing/stabilizing dimerization in living cells. Lastly, we demonstrate that this antibody promotes neurite outgrowth in SH-SY5Y cells. In summary, we demonstrated that the split luciferase RPTPσ activity assay is a novel high-throughput approach for discovering novel RPTPσ modulators that can promote axonal outgrowth and neural regeneration.

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Section: Discussionmentioning

confidence: 99%

Identification of function-regulating antibodies targeting the receptor protein tyrosine phosphatase sigma ectodomain

Hardy

Aubry

et al. 2017

PLoS ONE

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“…274 Compound 211 also dose-dependently reduced inflammation in the delayed-type hypersensitivity mouse model. 274 …”

Section: Therapeutic Targeting Of Ptp Regulatory Mechanismsmentioning

confidence: 93%

Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

Zhang

2017

Chem. Rev.

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Appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and keep cellular homeostasis. Faulty operation of signal pathways mediated by protein tyrosine phosphorylation causes numerous human diseases, which presents enormous opportunities for therapeutic interventions. While the importance of protein tyrosine kinases in orchestrating the tyrosine phosphorylation networks and in target-based drug discovery has long been recognized, the significance of protein tyrosine phosphatases (PTPs) in cellular signaling and disease biology has historically been underappreciated, due to a large extent an erroneous assumption that they are largely constitutive and housekeeping enzymes. Here, we provide a comprehensive examination on a number of regulatory mechanisms including redox modulation, allosteric regulation, and protein oligomerization, in controlling PTP activity. These regulatory mechanisms are integral to the myriad PTP-mediated biochemical events and reinforce the concept that PTPs are indispensable and specific modulators of cellular signaling. We also discuss how disruption of these PTP regulatory mechanisms can cause human diseases and how these diverse regulatory mechanisms can be exploited for novel therapeutic development.

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“…Compound 211 is a selective inhibitor of CD45 –a PTP that promotes antigen receptor signaling in lymphocytes and is considered a drug target for autoimmunity[44]- identified by in silico screening for compounds predicted to bind the interface between CD45-D1 and -D2 domains[45]. Compound 211 is an irreversible, non-competitive inhibitor.…”

Section: Trends In Small-molecule Ptp Inhibitor Developmentmentioning

confidence: 99%

“…A 3 mg/kg i.p. dose substantially reduced inflammation in the delayed-type hypersensitivity mouse model[45]. …”

Section: Trends In Small-molecule Ptp Inhibitor Developmentmentioning

confidence: 99%

Targeting Tyrosine Phosphatases: Time to End the Stigma

Stanford

Bottini

2017

Trends in Pharmacological Sciences

148

145

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Protein tyrosine phosphatases (PTPs) are a family of enzymes essential for numerous cellular processes, and several PTPs have been validated as therapeutic targets for human diseases. Historically, development of drugs targeting PTPs has been highly challenging, leading to stigmatization of these enzymes as undruggable targets. Despite these difficulties, efforts to drug PTPs have persisted, and recent years have seen an influx of new probes, providing opportunities for biological examination of old and new PTP targets. Here we will discuss progress towards drugging PTPs, with special emphasis on development of selective probes with biological activity. We will describe development of new small-molecule orthosteric, allosteric and oligomerization PTP inhibitors, and discuss new studies targeting the receptor PTP subfamily with biologics.

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Allosteric Noncompetitive Small Molecule Selective Inhibitors of CD45 Tyrosine Phosphatase Suppress T-Cell Receptor Signals and Inflammation In Vivo

Cited by 25 publications

References 42 publications

Identification of function-regulating antibodies targeting the receptor protein tyrosine phosphatase sigma ectodomain

Identification of function-regulating antibodies targeting the receptor protein tyrosine phosphatase sigma ectodomain

Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

Targeting Tyrosine Phosphatases: Time to End the Stigma

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