Abstract
The Janus kinase 2 (JAK2)-mediated signaling pathway plays an important role in controlling cell survival, proliferation, and differentiation. A mutation of JAK2 (V617F in specific) that results in constitutive activation of the enzyme is found in patients with myeloproliferative neoplasms (MPNs), such as polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis. The genetic, biological, and physiological evidence available to date has established JAK2 inhibitors as effective chemotherapeutic agents for the treatment of MPNs as well as solid tumors, hepatitis C virus (HCV) infection, Alzheimer’s disease, and Parkinson’s disease. Important features essential for JAK2 inhibitors are potent enzymatic inhibition and a high degree of selectivity among other isoforms of JAK. The extent of the potency and selectivity of JAK2 inhibitors is dependent upon receptor-ligand interactions and structural difference between isoenzymes. Thus, detailed knowledge regarding structural characteristics and the binding mode between JAK2 and its inhibitors is necessary. Accordingly, we compiled in this review a comprehensive summary of the three dimensional (3D) structural features of reported JAK2-ligand complexes and the structureactivity relationship (SAR) of JAK2 inhibitors, with particular focus on potent JAK2 inhibition and specificity.
Keywords: Hinge region, Janus kinase 2, type I JAK2 inhibitor, JAK2V617F mutation, JAK isoenzymes selectivity, myeloproliferative neoplasm.
Current Medicinal Chemistry
Title:Insights into the Structural Features Essential for JAK2 Inhibition and Selectivity
Volume: 23 Issue: 13
Author(s): Chao Zhao, Daulat Bikram Khadka and Won-Jea Cho
Affiliation:
Keywords: Hinge region, Janus kinase 2, type I JAK2 inhibitor, JAK2V617F mutation, JAK isoenzymes selectivity, myeloproliferative neoplasm.
Abstract: The Janus kinase 2 (JAK2)-mediated signaling pathway plays an important role in controlling cell survival, proliferation, and differentiation. A mutation of JAK2 (V617F in specific) that results in constitutive activation of the enzyme is found in patients with myeloproliferative neoplasms (MPNs), such as polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis. The genetic, biological, and physiological evidence available to date has established JAK2 inhibitors as effective chemotherapeutic agents for the treatment of MPNs as well as solid tumors, hepatitis C virus (HCV) infection, Alzheimer’s disease, and Parkinson’s disease. Important features essential for JAK2 inhibitors are potent enzymatic inhibition and a high degree of selectivity among other isoforms of JAK. The extent of the potency and selectivity of JAK2 inhibitors is dependent upon receptor-ligand interactions and structural difference between isoenzymes. Thus, detailed knowledge regarding structural characteristics and the binding mode between JAK2 and its inhibitors is necessary. Accordingly, we compiled in this review a comprehensive summary of the three dimensional (3D) structural features of reported JAK2-ligand complexes and the structureactivity relationship (SAR) of JAK2 inhibitors, with particular focus on potent JAK2 inhibition and specificity.
Export Options
About this article
Cite this article as:
Zhao Chao, Khadka Bikram Daulat and Cho Won-Jea, Insights into the Structural Features Essential for JAK2 Inhibition and Selectivity, Current Medicinal Chemistry 2016; 23 (13) . https://dx.doi.org/10.2174/0929867323666160405112615
DOI https://dx.doi.org/10.2174/0929867323666160405112615 |
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
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
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
Role of Growth Factors in the Pathogenesis of Tissue Fibrosis in Systemic Sclerosis
Current Rheumatology Reviews Tumor Stem Cell Niches: A New Functional Framework for the Action of Anticancer Drugs
Recent Patents on Anti-Cancer Drug Discovery Reviewing Colchicaceae Alkaloids – Perspectives of Evolution on Medicinal Chemistry
Current Topics in Medicinal Chemistry Voltage-Gated Ion Channels, New Targets in Anti-Cancer Research
Recent Patents on Anti-Cancer Drug Discovery Drug-Related Cardiotoxicity for the Treatment of Haematological Malignancies in Elderly
Current Pharmaceutical Design Exploring and Exploiting Biologically Relevant Chemical Space
Current Drug Targets Gemcitabine: A Critical Nucleoside for Cancer Therapy
Current Medicinal Chemistry Dendritoma Vaccine for Cancer: A Hopeful Approach
Current Cancer Therapy Reviews Sphingosine Kinases Signalling in Carcinogenesis
Mini-Reviews in Medicinal Chemistry Development and Assessment of Conventional and Targeted Drug Combinations for Use in the Treatment of Aggressive Breast Cancers
Current Cancer Drug Targets L1 Retrotransposon and Retinoblastoma: Molecular Linkages Between Epigenetics and Cancer
Current Molecular Medicine Advances in Stem Cell Therapy for Leukemia
Current Stem Cell Research & Therapy The Wnt Pathway: Emerging Anticancer Strategies
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Recent Developments in the Synthesis and Biological Activity of Muramylpeptides
Current Medicinal Chemistry Synthesis and Evaluation of 2-Substituted Fendiline Analogues as Antileukemics
Letters in Drug Design & Discovery Nucleoside Transporter Proteins
Current Vascular Pharmacology The Ubiquitin+Proteasome Protein Degradation Pathway as a Therapeutic Strategy in the Treatment of Solid Tumor Malignancies
Anti-Cancer Agents in Medicinal Chemistry Identification of Novel Potent Inhibitors Against Bcl-xL Anti-apoptotic Protein Using Docking Studies
Protein & Peptide Letters Quercetin Promotes Cell Cycle Arrest and Apoptosis and Attenuates the Proliferation of Human Chronic Myeloid Leukemia Cell Line-K562 Through Interaction with HSPs (70 and 90), MAT2A and FOXM1
Anti-Cancer Agents in Medicinal Chemistry Emerging Role of the Ubiquitin-proteasome System as Drug Targets
Current Pharmaceutical Design