Abstract
MAP kinase-interacting kinases (MNK1 and MNK2) are often activated downstream of ERK and p38 MAPK in the MAP kinase family. The role of MNKs in the development and progression of solid tumors and hematological malignancies has been widely discussed, particularly in the context of cap dependent translation, regulated by phosphorylation of eIF4E. MNK/eIF4E axis is involved in the expression of pro angiogenic, antiapoptotic, cell cycle, and motility proteins, such as MCL1, VEGF, MMP3, SNAIL, SMAD2, β-catenin or cyclin D1, and is essential during Ras and c Myc-induced transformation. MNK1/2 emerged as eligible targets for drug discovery in oncology, based on the antitumor effects observed in genetic knockout and RNA interference experiments and at the same time lack of adverse effects in dual knockout animals.
There is a high interest in the development of pharmacological inhibitors of MNK1/2 as not only tools for further basic research studies but also potential drugs in diseases characterized by deregulated translation. Unfortunately, the role of MNK1/2 in cancer still remains elusive due to the absence of potent and selective probes. Moreover, in many instances, hypotheses have been built reliant upon unspecific MNK1/2 inhibitors such as CGP57380 or cercosporamide. Lately, the first two clinical programs targeting MNKs in oncology have been revealed (eFT508 and BAY 1143269), although several other MNK programs are currently running at the preclinical stage. This review aims to provide an overview of recent progress in the development of MNK inhibitors.
Keywords: Protein kinase, kinase inhibitors, drug discovery, MNK1 MNK2, cancer, small molecule, eIF4E phosphorylation.
Current Medicinal Chemistry
Title:Mitogen-activated Protein Kinase (MAPK) Interacting Kinases 1 and 2 (MNK1 and MNK2) as Targets for Cancer Therapy: Recent Progress in the Development of MNK Inhibitors
Volume: 24 Issue: 28
Author(s): Agnieszka Dreas, Maciej Mikulski, Mariusz Milik, Charles-Henry Fabritius, Krzysztof Brzózka and Tomasz Rzymski*
Affiliation:
- Selvita S.A. Bobrzyńskiego 14, 30-348 Kraków,Poland
Keywords: Protein kinase, kinase inhibitors, drug discovery, MNK1 MNK2, cancer, small molecule, eIF4E phosphorylation.
Abstract: MAP kinase-interacting kinases (MNK1 and MNK2) are often activated downstream of ERK and p38 MAPK in the MAP kinase family. The role of MNKs in the development and progression of solid tumors and hematological malignancies has been widely discussed, particularly in the context of cap dependent translation, regulated by phosphorylation of eIF4E. MNK/eIF4E axis is involved in the expression of pro angiogenic, antiapoptotic, cell cycle, and motility proteins, such as MCL1, VEGF, MMP3, SNAIL, SMAD2, β-catenin or cyclin D1, and is essential during Ras and c Myc-induced transformation. MNK1/2 emerged as eligible targets for drug discovery in oncology, based on the antitumor effects observed in genetic knockout and RNA interference experiments and at the same time lack of adverse effects in dual knockout animals.
There is a high interest in the development of pharmacological inhibitors of MNK1/2 as not only tools for further basic research studies but also potential drugs in diseases characterized by deregulated translation. Unfortunately, the role of MNK1/2 in cancer still remains elusive due to the absence of potent and selective probes. Moreover, in many instances, hypotheses have been built reliant upon unspecific MNK1/2 inhibitors such as CGP57380 or cercosporamide. Lately, the first two clinical programs targeting MNKs in oncology have been revealed (eFT508 and BAY 1143269), although several other MNK programs are currently running at the preclinical stage. This review aims to provide an overview of recent progress in the development of MNK inhibitors.
Export Options
About this article
Cite this article as:
Dreas Agnieszka, Mikulski Maciej, Milik Mariusz, Fabritius Charles-Henry, Brzózka Krzysztof and Rzymski Tomasz*, Mitogen-activated Protein Kinase (MAPK) Interacting Kinases 1 and 2 (MNK1 and MNK2) as Targets for Cancer Therapy: Recent Progress in the Development of MNK Inhibitors, Current Medicinal Chemistry 2017; 24 (28) . https://dx.doi.org/10.2174/0929867324666170203123427
DOI https://dx.doi.org/10.2174/0929867324666170203123427 |
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
-
Bone Seeking Radiopharmaceuticals for Palliation of Pain in Cancer Patients with Osseous Metastases
Anti-Cancer Agents in Medicinal Chemistry Prognostic Parameters in Myeloid Malignancies in a Historical Context – From Microscopy to Individualized Medicine
Current Drug Targets Multifunctional Anti-Cancer Nano-Platforms are Moving to Clinical Trials
Current Drug Metabolism CX-4945, a Selective Inhibitor of Casein Kinase 2, Synergizes with B Cell Receptor Signaling Inhibitors in Inducing Diffuse Large B Cell Lymphoma Cell Death
Current Cancer Drug Targets Irinotecan for Treatment of Childhood Cancers: A Promising Therapeutic Partner
Current Cancer Therapy Reviews Epigenetic Remodeling of Chromatin Architecture: Exploring Tumor Differentiation Therapies in Mesenchymal Stem Cells and Sarcomas
Current Stem Cell Research & Therapy Anti-Angiogenesis in the Treatment of Genito-Urinary Cancers: Last Updates
Current Angiogenesis (Discontinued) miR-629-3p Level Significantly Predicts Prognosis in Glioblastoma Patients Treated with Temozolomide Chemotherapy
Current Signal Transduction Therapy Interferon Treatment in Patients with Hypereosinophilia
Current Drug Targets Small-molecule Inhibitors of Epigenetic Mutations as Compelling Drugtargets for Myelodysplastic Syndromes
Current Cancer Drug Targets Current Status of Leukemia Cytotherapy - Exploitation with Immune Cells
Current Stem Cell Research & Therapy Reversal of Resistance to Oxazaphosphorines
Current Cancer Drug Targets Targeted Therapy of Breast Cancer
Current Pharmaceutical Design Hematopoietic Stem Cells: Source Matters
Current Stem Cell Research & Therapy Short- and Long-Term Survival of Nonsurgical Intensive Care Patients and its Relation to Diagnosis, Severity of Disease, Age and Comorbidities
Current Aging Science Chemical and Clinical Development of Darinaparsin, a Novel Organic Arsenic Derivative
Anti-Cancer Agents in Medicinal Chemistry Clinical Applications of Gene Therapy in Head and Neck Cancer
Current Gene Therapy B Lymphocytes, Potent Antigen Presenting Cells for Preferential Expansion of Allo-Reactive FoxP3+ CD4 Regulatory T Cells
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery The Use of Interferons in Respiratory Diseases
Current Respiratory Medicine Reviews Systemic Treatments for Adult Patients with Moderate-to-Severe Psoriasis: Consensus Statements for the United Arab Emirates
New Emirates Medical Journal