Abstract
Mitogen-activated protein kinase phosphatases (MKPs) are dual specificity protein phosphatases (DUSPs) that dephosphorylate both phospho-tyrosine and phospho-threonine residues on mitogen-activated protein kinases (MAPKs). Because the MAPK family of signalling molecules (phospho-p38 MAPK, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)) play essential roles in cell signalling pathways that regulate cell growth and inflammation, controlling MAPK-mediated pathways is a therapeutically attractive strategy. While small molecule MAPK inhibitors have utility, in this review we will focus on exploring the potential of targeting the endogenous MAPK deactivator - MKP-1. Importantly, there is a strong justification for developing both inhibitors and upregulators of MKP-1 because of the diverse roles played by MAPKs in disease: for example, in cancer, MKP-1 inhibitors may prove beneficial, as MKP-1 is overexpressed and is considered responsible for the failure of JNK-driven apoptotic pathways induced by chemotherapeutics; conversely, in inflammatory diseases such as asthma and arthritis, MKP-1 reduces MAPKmediated signalling and developing novel ligands to upregulate MKP-1 levels would be a therapeutically attractive anti-inflammatory strategy. Thus, in this review we utilise MKP-1 homology modeling to highlight the structural features of MKP-1 inhibitors that permit potent and selective inhibition, and to provide insights into the structural requirements for selective MKP-1 upregulators.
Keywords: MKP-1, DUSP1, MAPK, inflammatory disease, asthma, cancer, arthritis, homology model, small molecule inhibitors, ubiquitinproteasome system
Current Medicinal Chemistry
Title: Targeting Mitogen-Activated Protein Kinase Phosphatase-1 (MKP-1): Structure-Based Design of MKP-1 Inhibitors and Upregulators
Volume: 19 Issue: 2
Author(s): M. R. Doddareddy, T. Rawling and A. J. Ammit
Affiliation:
Keywords: MKP-1, DUSP1, MAPK, inflammatory disease, asthma, cancer, arthritis, homology model, small molecule inhibitors, ubiquitinproteasome system
Abstract: Mitogen-activated protein kinase phosphatases (MKPs) are dual specificity protein phosphatases (DUSPs) that dephosphorylate both phospho-tyrosine and phospho-threonine residues on mitogen-activated protein kinases (MAPKs). Because the MAPK family of signalling molecules (phospho-p38 MAPK, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)) play essential roles in cell signalling pathways that regulate cell growth and inflammation, controlling MAPK-mediated pathways is a therapeutically attractive strategy. While small molecule MAPK inhibitors have utility, in this review we will focus on exploring the potential of targeting the endogenous MAPK deactivator - MKP-1. Importantly, there is a strong justification for developing both inhibitors and upregulators of MKP-1 because of the diverse roles played by MAPKs in disease: for example, in cancer, MKP-1 inhibitors may prove beneficial, as MKP-1 is overexpressed and is considered responsible for the failure of JNK-driven apoptotic pathways induced by chemotherapeutics; conversely, in inflammatory diseases such as asthma and arthritis, MKP-1 reduces MAPKmediated signalling and developing novel ligands to upregulate MKP-1 levels would be a therapeutically attractive anti-inflammatory strategy. Thus, in this review we utilise MKP-1 homology modeling to highlight the structural features of MKP-1 inhibitors that permit potent and selective inhibition, and to provide insights into the structural requirements for selective MKP-1 upregulators.
Export Options
About this article
Cite this article as:
R. Doddareddy M., Rawling T. and J. Ammit A., Targeting Mitogen-Activated Protein Kinase Phosphatase-1 (MKP-1): Structure-Based Design of MKP-1 Inhibitors and Upregulators, Current Medicinal Chemistry 2012; 19 (2) . https://dx.doi.org/10.2174/092986712803414196
DOI https://dx.doi.org/10.2174/092986712803414196 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Thermostable Subunit Vaccines for Pulmonary Delivery: How Close Are We?
Current Pharmaceutical Design Lipoxygenase Inhibitors for Cancer Prevention: Promises and Risks
Current Pharmaceutical Design Neuroprotective Activities of Orientin: A Review
Current Traditional Medicine Correlating Low-Similarity Peptide Sequences and Allergenic Epitopes
Current Pharmaceutical Design Heme Oxygenase-1/CO as Protective Mediators in Cigarette Smoke- Induced Lung Cell Injury and Chronic Obstructive Pulmonary Disease
Current Pharmaceutical Biotechnology Microwave-Assisted Chemistry of 2(1H)-pyrazinones
Current Organic Chemistry Immunoadjunctive Therapy against Bacterial Infections Using Herbal Medicines Based on Th17 Cell-mediated Protective Immunity
Current Pharmaceutical Design Fractional Exhaled Nitric Oxide and Nanomaterial Exposure in Workplaces
Current Medicinal Chemistry Diagnosis and Treatment of Alzheimers Disease
Current Medicinal Chemistry - Central Nervous System Agents Trafficking Potentials of Unconventional T Cell Subsets
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Some Aspects on Comparative Efficacy Studies with Inhaled Corticosteroids in Asthma
Current Drug Therapy The Central Role of Macrophages in Trypanosomiasis-Associated Anemia:Rationale for Therapeutical Approaches
Endocrine, Metabolic & Immune Disorders - Drug Targets Granulocyte Apoptosis and Macrophage Clearance of Apoptotic Cells as Targets for Pharmacological Intervention in Inflammatory Diseases
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry SAGE Application in Hematological Research
Current Pharmaceutical Biotechnology Importance of Zinc in Cystic Fibrosis Patients
Current Pediatric Reviews Recombinant Antibody Fragments for Neurodegenerative Diseases
Current Neuropharmacology Inhalation Delivery of Protein Therapeutics
Inflammation & Allergy - Drug Targets (Discontinued) The Need to Consider Context in the Evaluation of Anti-infectious and Immunomodulatory Effects of Vitamin A and its Derivatives
Current Drug Targets PLA2 Mediated Arachidonate Free Radicals: PLA2 Inhibition and Neutralization of Free Radicals by Anti-Oxidants – A New Role as Anti-Inflammatory Molecule
Current Topics in Medicinal Chemistry Therapeutic Potential of Agonists and Antagonists of A1, A2a, A2b and A3 Adenosine Receptors
Current Pharmaceutical Design