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Special Issue "Protein-Tyrosine Phosphatase Inhibitors"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (30 January 2018)

Special Issue Editors

Guest Editor
Prof. Jeroen den Hertog

1. Hubrecht Institute–Koninklijke Nederlandse Akademie van Wetenschappen (KNAW) and University Medical Center Utrecht, Utrecht, The Netherlands
2. Institute of Biology Leiden, Leiden University, Leiden, The Netherlands
Website | E-Mail
Interests: protein-tyrosine phosphatase; signaling; PTEN; SHP2; RPTPalpha; zebrafish; gastrulation; cancer; Noonan Syndrome
Guest Editor
Prof. Rob M. J. Liskamp

School of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow, UK and Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
Website 1 | Website 2 | E-Mail
Interests: peptidomimetics; protein mimics; synthetic vaccines; synthetic antibodies; protease inhibitors; protein phosphatase inhibitors; electrophilic traps; cancer; infections; inflammation

Special Issue Information

Dear Colleagues,

Protein-tyrosine phosphatases counteract protein-tyrosine kinases and, hence, have a central role in development and disease, as regulators of phosphotyrosine levels in cellular proteins. Protein-tyrosine phosphatases have been heralded as drug targets for decades, particularly for conditions such as cancer and diabetes. Over the years, many catalytic site-directed protein-tyrosine phosphatase inhibitors have been generated; however, the catalytic sites of protein-tyrosine phosphatases are highly conserved, which compromises the selectivity of small molecule compounds. In addition, the substrates of protein-tyrosine phosphatases contain negatively-charged phosphotyrosine, which hampers the transduction of substrate-mimetic inhibitors across the cell membrane. Recently, several allosteric inhibitors have been developed that are highly selective and do not contain negative charges. Looking forward, there is a bright future for small molecule inhibitors of protein-tyrosine phosphatases.

Prof.  Jeroen den Hertog
Prof. Rob M. J. Liskamp
Guest Editors

Manuscript Submission Information

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Keywords

  • protein-tyrosine phosphatases
  • (covalent) inhibitors
  • small molecules
  • peptidomimetics
  • allosteric inhibitors
  • cancer
  • diabetes

Published Papers (6 papers)

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Research

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Open AccessArticle VSpipe, an Integrated Resource for Virtual Screening and Hit Selection: Applications to Protein Tyrosine Phospahatase Inhibition
Molecules 2018, 23(2), 353; https://doi.org/10.3390/molecules23020353
Received: 20 December 2017 / Revised: 2 February 2018 / Accepted: 4 February 2018 / Published: 7 February 2018
PDF Full-text (3333 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The use of computational tools for virtual screening provides a cost-efficient approach to select starting points for drug development. We have developed VSpipe, a user-friendly semi-automated pipeline for structure-based virtual screening. VSpipe uses the existing tools AutoDock and OpenBabel together with software developed
[...] Read more.
The use of computational tools for virtual screening provides a cost-efficient approach to select starting points for drug development. We have developed VSpipe, a user-friendly semi-automated pipeline for structure-based virtual screening. VSpipe uses the existing tools AutoDock and OpenBabel together with software developed in-house, to create an end-to-end virtual screening workflow ranging from the preparation of receptor and ligands to the visualisation of results. VSpipe is efficient and flexible, allowing the users to make choices at different steps, and it is amenable to use in both local and cluster mode. We have validated VSpipe using the human protein tyrosine phosphatase PTP1B as a case study. Using a combination of blind and targeted docking VSpipe identified both new and known functional ligand binding sites. Assessment of different binding clusters using the ligand efficiency plots created by VSpipe, defined a drug-like chemical space for development of PTP1B inhibitors with potential applications to other PTPs. In this study, we show that VSpipe can be deployed to identify and compare different modes of inhibition thus guiding the selection of initial hits for drug discovery. Full article
(This article belongs to the Special Issue Protein-Tyrosine Phosphatase Inhibitors)
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Open AccessArticle Novel Mixed-Type Inhibitors of Protein Tyrosine Phosphatase 1B. Kinetic and Computational Studies
Molecules 2017, 22(12), 2262; https://doi.org/10.3390/molecules22122262
Received: 21 November 2017 / Revised: 13 December 2017 / Accepted: 16 December 2017 / Published: 20 December 2017
PDF Full-text (3892 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The Atlas of Diabetes reports 415 million diabetics in the world, a number that has surpassed in half the expected time the twenty year projection. Type 2 diabetes is the most frequent form of the disease; it is characterized by a defect in
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The Atlas of Diabetes reports 415 million diabetics in the world, a number that has surpassed in half the expected time the twenty year projection. Type 2 diabetes is the most frequent form of the disease; it is characterized by a defect in the secretion of insulin and a resistance in its target organs. In the search for new antidiabetic drugs, one of the principal strategies consists in promoting the action of insulin. In this sense, attention has been centered in the protein tyrosine phosphatase 1B (PTP1B), a protein whose overexpression or increase of its activity has been related in many studies with insulin resistance. In the present work, a chemical library of 250 compounds was evaluated to determine their inhibition capability on the protein PTP1B. Ten molecules inhibited over the 50% of the activity of the PTP1B, the three most potent molecules were selected for its characterization, reporting Ki values of 5.2, 4.2 and 41.3 µM, for compounds 1, 2, and 3, respectively. Docking and molecular dynamics studies revealed that the three inhibitors made interactions with residues at the secondary binding site to phosphate, exclusive for PTP1B. The data reported here support these compounds as hits for the design more potent and selective inhibitors against PTP1B in the search of new antidiabetic treatment. Full article
(This article belongs to the Special Issue Protein-Tyrosine Phosphatase Inhibitors)
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Review

Jump to: Research

Open AccessReview Targeting Receptor-Type Protein Tyrosine Phosphatases with Biotherapeutics: Is Outside-in Better than Inside-Out?
Molecules 2018, 23(3), 569; https://doi.org/10.3390/molecules23030569
Received: 30 January 2018 / Revised: 26 February 2018 / Accepted: 26 February 2018 / Published: 2 March 2018
Cited by 1 | PDF Full-text (6815 KB) | HTML Full-text | XML Full-text
Abstract
Protein tyrosine phosphatases (PTPs), of the receptor and non-receptor classes, are key signaling molecules that play critical roles in cellular regulation underlying diverse physiological events. Aberrant signaling as a result of genetic mutation or altered expression levels has been associated with several diseases
[...] Read more.
Protein tyrosine phosphatases (PTPs), of the receptor and non-receptor classes, are key signaling molecules that play critical roles in cellular regulation underlying diverse physiological events. Aberrant signaling as a result of genetic mutation or altered expression levels has been associated with several diseases and treatment via pharmacological intervention at the level of PTPs has been widely explored; however, the challenges associated with development of small molecule phosphatase inhibitors targeting the intracellular phosphatase domain (the “inside-out” approach) have been well documented and as yet there are no clinically approved drugs targeting these enzymes. The alternative approach of targeting receptor PTPs with biotherapeutic agents (such as monoclonal antibodies or engineered fusion proteins; the “outside-in” approach) that interact with the extracellular ectodomain offers many advantages, and there have been a number of exciting recent developments in this field. Here we provide a brief overview of the receptor PTP family and an update on the emerging area of receptor PTP-targeted biotherapeutics for CD148, vascular endothelial-protein tyrosine phosphatase (VE-PTP), receptor-type PTPs σ, γ, ζ (RPTPσ, RPTPγ, RPTPζ) and CD45, and discussion of future potential in this area. Full article
(This article belongs to the Special Issue Protein-Tyrosine Phosphatase Inhibitors)
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Open AccessReview Proteinaceous Regulators and Inhibitors of Protein Tyrosine Phosphatases
Molecules 2018, 23(2), 395; https://doi.org/10.3390/molecules23020395
Received: 23 January 2018 / Revised: 9 February 2018 / Accepted: 9 February 2018 / Published: 12 February 2018
Cited by 3 | PDF Full-text (2660 KB) | HTML Full-text | XML Full-text
Abstract
Proper control of the phosphotyrosine content in signal transduction proteins is essential for normal cell behavior and is lost in many pathologies. Attempts to normalize aberrant tyrosine phosphorylation levels in disease states currently involve either the application of small compounds that inhibit tyrosine
[...] Read more.
Proper control of the phosphotyrosine content in signal transduction proteins is essential for normal cell behavior and is lost in many pathologies. Attempts to normalize aberrant tyrosine phosphorylation levels in disease states currently involve either the application of small compounds that inhibit tyrosine kinases (TKs) or the addition of growth factors or their mimetics to boost receptor-type TK activity. Therapies that target the TK enzymatic counterparts, the multi-enzyme family of protein tyrosine phosphatases (PTPs), are still lacking despite their undisputed involvement in human diseases. Efforts to pharmacologically modulate PTP activity have been frustrated by the conserved structure of the PTP catalytic core, providing a daunting problem with respect to target specificity. Over the years, however, many different protein interaction-based regulatory mechanisms that control PTP activity have been uncovered, providing alternative possibilities to control PTPs individually. Here, we review these regulatory principles, discuss existing biologics and proteinaceous compounds that affect PTP activity, and mention future opportunities to drug PTPs via these regulatory concepts. Full article
(This article belongs to the Special Issue Protein-Tyrosine Phosphatase Inhibitors)
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Open AccessReview PTEN Inhibition in Human Disease Therapy
Molecules 2018, 23(2), 285; https://doi.org/10.3390/molecules23020285
Received: 10 January 2018 / Revised: 26 January 2018 / Accepted: 28 January 2018 / Published: 30 January 2018
Cited by 1 | PDF Full-text (2218 KB) | HTML Full-text | XML Full-text
Abstract
The tumor suppressor PTEN is a major homeostatic regulator, by virtue of its lipid phosphatase activity against phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], which downregulates the PI3K/AKT/mTOR prosurvival signaling, as well as by its protein phosphatase activity towards specific protein targets. PTEN catalytic activity is crucial
[...] Read more.
The tumor suppressor PTEN is a major homeostatic regulator, by virtue of its lipid phosphatase activity against phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], which downregulates the PI3K/AKT/mTOR prosurvival signaling, as well as by its protein phosphatase activity towards specific protein targets. PTEN catalytic activity is crucial to control cell growth under physiologic and pathologic situations, and it impacts not only in preventing tumor cell survival and proliferation, but also in restraining several cellular regeneration processes, such as those associated with nerve injury recovery, cardiac ischemia, or wound healing. In these conditions, inhibition of PTEN catalysis is being explored as a potentially beneficial therapeutic intervention. Here, an overview of human diseases and conditions in which PTEN inhibition could be beneficial is presented, together with an update on the current status of specific small molecule inhibitors of PTEN enzymatic activity, their use in experimental models, and their limitations as research or therapeutic drugs. Full article
(This article belongs to the Special Issue Protein-Tyrosine Phosphatase Inhibitors)
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Open AccessReview Vanadium Compounds as PTP Inhibitors
Molecules 2017, 22(12), 2269; https://doi.org/10.3390/molecules22122269
Received: 30 November 2017 / Revised: 14 December 2017 / Accepted: 15 December 2017 / Published: 19 December 2017
Cited by 2 | PDF Full-text (2642 KB) | HTML Full-text | XML Full-text
Abstract
Phosphotyrosine signaling is regulated by the opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Here we discuss the potential of vanadium derivatives as PTP enzyme inhibitors and metallotherapeutics. We describe how vanadate in the V oxidized state is thought
[...] Read more.
Phosphotyrosine signaling is regulated by the opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Here we discuss the potential of vanadium derivatives as PTP enzyme inhibitors and metallotherapeutics. We describe how vanadate in the V oxidized state is thought to inhibit PTPs, thus acting as a pan-inhibitor of this enzyme superfamily. We discuss recent developments in the biological and biochemical actions of more complex vanadium derivatives, including decavanadate and in particular the growing number of oxidovanadium compounds with organic ligands. Pre-clinical studies involving these compounds are discussed in the anti-diabetic and anti-cancer contexts. Although in many cases PTP inhibition has been implicated, it is also clear that many such compounds have further biochemical effects in cells. There also remain concerns surrounding off-target toxicities and long-term use of vanadium compounds in vivo in humans, hindering their progress through clinical trials. Despite these current misgivings, interest in these chemicals continues and many believe they could still have therapeutic potential. If so, we argue that this field would benefit from greater focus on improving the delivery and tissue targeting of vanadium compounds in order to minimize off-target toxicities. This may then harness their full therapeutic potential. Full article
(This article belongs to the Special Issue Protein-Tyrosine Phosphatase Inhibitors)
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