Document Detail

Therapeutic potential of JAK2 inhibitors.
MedLine Citation:
PMID:  20008249     Owner:  NLM     Status:  MEDLINE    
The discovery of an activating tyrosine kinase mutation JAK2V617F in myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) has resulted in the development of JAK2 inhibitors, of which several are being evaluated in phase I/II clinical studies. It is important to recognize that because the V617F mutation is localized in a region outside the adenosine triphosphate (ATP)-binding pocket of JAK2 enzyme, ATP-competitive inhibitors of JAK2 kinase (like the current JAK2 inhibitors in the clinic) are not likely to discriminate between wild-type and mutant JAK2 enzymes. Therefore, JAK2 inhibitors, by virtue of their near equipotent activity against wild-type JAK2 that is important for normal hematopoiesis, may have adverse myelosuppression as an expected side effect, if administered at doses that aim to completely inhibit the mutant JAK2 enzyme. While they may prove to be effective in controlling hyperproliferation of hematopoietic cells in PV and ET, they may not be able to eliminate mutant clones. On the other hand, JAK inhibitors may have great therapeutic benefit by controlling the disease for patients with MPNs who suffer from debilitating signs (eg, splenomegaly) or constitutional symptoms (which presumably result from high levels of circulating cytokines that signal through JAK enzymes). Indeed, the primary clinical benefits observed so far in MF patients have been significant reduction is splenomegaly, elimination of debilitating disease-related symptoms, and weight gain. Most importantly, patients with and without the JAK2V617F mutation appear to benefit to the same extent. In this review we summarize current clinical experience with JAK2 inhibitors in MPNs.
Srdan Verstovsek
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program     Volume:  -     ISSN:  1520-4383     ISO Abbreviation:  Hematology Am Soc Hematol Educ Program     Publication Date:  2009  
Date Detail:
Created Date:  2009-12-16     Completed Date:  2010-03-15     Revised Date:  2012-06-05    
Medline Journal Info:
Nlm Unique ID:  100890099     Medline TA:  Hematology Am Soc Hematol Educ Program     Country:  United States    
Other Details:
Languages:  eng     Pagination:  636-42     Citation Subset:  IM    
The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
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MeSH Terms
Carbazoles / therapeutic use
Clinical Trials as Topic
Drug Delivery Systems
Drug Evaluation, Preclinical
Janus Kinase 2 / antagonists & inhibitors*,  genetics
Mutation, Missense
Myeloproliferative Disorders / drug therapy*,  enzymology,  genetics
Point Mutation
Protein Kinase Inhibitors / therapeutic use*
Pyrazoles / therapeutic use
Pyrrolidines / therapeutic use
Signal Transduction / drug effects
Splenomegaly / drug therapy,  etiology
Sulfonamides / therapeutic use
Weight Gain
Reg. No./Substance:
0/Carbazoles; 0/INCB018424; 0/Protein Kinase Inhibitors; 0/Pyrazoles; 0/Pyrrolidines; 0/Sulfonamides; 0/TG101348; 0/lestaurtinib; EC Kinase 2; EC protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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