Abstract
An activating mutation (V617F) in the pseudokinase domain of the Janus kinase (JAK)-2 tyrosine kinase has been described in 90% of patients with polycythemia vera (PV) and 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (MF). The discovery of JAK2V617F stirred the development of JAK2 inhibitors for treatment of patients with MF, ET and PV. Similar to other tyrosine kinase (TK) inhibitors in current use, JAK2 inhibitors target the adenosine triphosphate (ATP) binding site at the TK domain and not the pseudokinase domain, thus affecting both mutated and wild-type kinases. In fact, clinical trials of these compounds have demonstrated improvements in constitutional symptoms and splenomegaly in patients with both mutated and wild-type JAK2 MF. It is believed that these drugs may act not only through inhibition of neoplastic cell proliferation, but also by downregulating signaling through proinflammatory cytokine receptors. In this article, we review the current state of JAK2 inhibitors and discuss why these drugs could be a valuable addition to the treatment armamentarium for patients with and without the JAK2V617F mutation.
Keywords: Essential thrombocythemia, JAK2 inhibitor, JAK2V617F, Myelofibrosis, Polycythemia vera, CYTOKINE RECEPTORS, JAK TYROSINE KINASES, proinflammatory state, erythropoietin, microenvironmental cells
Anti-Cancer Agents in Medicinal Chemistry
Title:JAK2 Inhibitors for Myelofibrosis: Why are They Effective in Patients with and Without JAK2V617F Mutation?
Volume: 12 Issue: 9
Author(s): Fabio P. S. Santos and Srdan Verstovsek
Affiliation:
Keywords: Essential thrombocythemia, JAK2 inhibitor, JAK2V617F, Myelofibrosis, Polycythemia vera, CYTOKINE RECEPTORS, JAK TYROSINE KINASES, proinflammatory state, erythropoietin, microenvironmental cells
Abstract: An activating mutation (V617F) in the pseudokinase domain of the Janus kinase (JAK)-2 tyrosine kinase has been described in 90% of patients with polycythemia vera (PV) and 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (MF). The discovery of JAK2V617F stirred the development of JAK2 inhibitors for treatment of patients with MF, ET and PV. Similar to other tyrosine kinase (TK) inhibitors in current use, JAK2 inhibitors target the adenosine triphosphate (ATP) binding site at the TK domain and not the pseudokinase domain, thus affecting both mutated and wild-type kinases. In fact, clinical trials of these compounds have demonstrated improvements in constitutional symptoms and splenomegaly in patients with both mutated and wild-type JAK2 MF. It is believed that these drugs may act not only through inhibition of neoplastic cell proliferation, but also by downregulating signaling through proinflammatory cytokine receptors. In this article, we review the current state of JAK2 inhibitors and discuss why these drugs could be a valuable addition to the treatment armamentarium for patients with and without the JAK2V617F mutation.
Export Options
About this article
Cite this article as:
P. S. Santos Fabio and Verstovsek Srdan, JAK2 Inhibitors for Myelofibrosis: Why are They Effective in Patients with and Without JAK2V617F Mutation?, Anti-Cancer Agents in Medicinal Chemistry 2012; 12 (9) . https://dx.doi.org/10.2174/187152012803529727
DOI https://dx.doi.org/10.2174/187152012803529727 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
- 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
Related Articles
-
The Optimal Treatment of Severe Hypertension in Pregnancy: Update of the Role of Nicardipine
Current Pharmaceutical Biotechnology Vitamin D Measurement in the Intensive Care Unit: Methodology, Clinical Relevance and Interpretation of a Random Value
Inflammation & Allergy - Drug Targets (Discontinued) Pain Management in Hematological Patients with Major Organ Dysfunctions and Comorbid Illnesses
Cardiovascular & Hematological Agents in Medicinal Chemistry Stroke Subtypes and their Possible Implication in Stroke Prevention Drug Strategies
Current Vascular Pharmacology State of the Art in Medical and Surgical Management of Pneumothorax
Current Respiratory Medicine Reviews New Indications for Corticosteroids in Intensive Care Units
Current Drug Targets Novel Strategies in the Treatment of Pulmonary Arterial Hypertension
Current Drug Targets Empagliflozin and the Diabetic Kidney: Pathophysiological Concepts and Future Challenges
Endocrine, Metabolic & Immune Disorders - Drug Targets Biochemical Strategies to Anticoagulation: A Comparative Overview
Current Vascular Pharmacology Research Advances in Neuroblastoma Immunotherapy
Current Pediatric Reviews Monoamine Oxidases: to Inhibit or Not to Inhibit
Mini-Reviews in Medicinal Chemistry A Safe and Novel Desensitization Protocol with Ferric Carboxymaltose to Treat Iron Deficiency Anemia
Current Drug Safety Pharmacokinetics of Topical Ocular Drug Delivery: Potential Uses for the Treatment of Diseases of the Posterior Segment and Beyond
Current Drug Metabolism Role of Adiponectin in Obesity, Hypertension, and Metabolic Syndrome
Current Hypertension Reviews Cardiotoxicity of Molecularly Targeted Agents
Current Cardiology Reviews Bisthiourea Derivatives of Dipeptide Conjugated Benzo[d]isoxazole as a New Class of Therapeutics: Synthesis and Molecular Docking Studies
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry The Role of Venous Abnormalities in Neurological Disease
Reviews on Recent Clinical Trials Selenium and Selenoproteins: An Overview on Different Biological Systems
Current Protein & Peptide Science Neuropeptide Mimetics and Antagonists in the Treatment of Inflammatory Disease: Focus on VIP and PACAP
Current Topics in Medicinal Chemistry Downregulation of Membrane-bound Angiotensin Converting Enzyme 2 (ACE2) Receptor has a Pivotal Role in COVID-19 Immunopathology
Current Drug Targets