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 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...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
Related Articles
-
Endocannabinoids and their Involvement in the Neurovascular System
Current Neurovascular Research Electroporation in DNA Vaccination Protocols Against Cancer
Current Drug Metabolism <i>Ralstonia Mannitolilytica</i>, an Unusual Pathogen in the Neonatal Intensive Care Unit: A Case of Neonatal Sepsis and Literature Review
Infectious Disorders - Drug Targets Systematic Review on Infusion Reactions Associated with Chemotherapies and Monoclonal Antibodies for Metastatic Colorectal Cancer
Current Clinical Pharmacology Platelets and Atherothrombosis: Causes, Targets and Treatments for Thrombosis
Current Medicinal Chemistry Seeds as a Production System for Molecular Pharming Applications: Status and Prospects
Current Pharmaceutical Design Variability in Response to Cardiovascular Drugs
Current Clinical Pharmacology Current Management of Intermittent Claudication: The Role of Pharmacological and Nonpharmacological Symptom-Directed Therapies
Current Vascular Pharmacology Inflammation and Anemia
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Small Molecules as Anti-TNF Drugs
Current Medicinal Chemistry Novel Metal Nanoparticles Stabilized with (2R,4R)-2,4-bis(diphenylphosphino) Pentane on SiO2. Their Use as Catalysts in Enantioselective Hydrogenation Reactions
Current Organic Chemistry Induction and Amelioration of Environmental Stress in Isolated Islets Until Transplantation
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Nutritional Control, Gene Regulation, and Transformation of Vascular Smooth Muscle Cells in Atherosclerosis
Cardiovascular & Hematological Disorders-Drug Targets Tako-tsubo Cardiomyopathy: A Review of the Literature
Current Cardiology Reviews Identification of Novel Anti-inflammatory Agents from Ayurvedic Medicine for Prevention of Chronic Diseases: “Reverse Pharmacology” and “Bedside to Bench” Approach
Current Drug Targets Recent Advances in the Synthesis of Naturally Occurring Polyhydroxylated Alkaloids
Current Organic Chemistry Therapeutic Challenges in Neuroendocrine Tumors
Anti-Cancer Agents in Medicinal Chemistry Barker and Brenner: A Basis for Hypertension?
Current Hypertension Reviews Current and Emerging Therapies in Neuroendocrine Tumors: Impact of Genetic Targets on Clinical Outcomes
Clinical Cancer Drugs Bioactive Peptides in Preventative Healthcare: An Overview of Bioactivities and Suggested Methods to Assess Potential Applications
Current Pharmaceutical Design