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.
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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 |
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