JAK2 the future: Therapeutic strategies for JAK-dependent malignancies Journal Article


Authors: LaFave, L. M.; Levine, R. L.
Article Title: JAK2 the future: Therapeutic strategies for JAK-dependent malignancies
Abstract: The Janus kinase (JAK) proteins are a family of intracellular nonreceptor tyrosine kinases involved in cytokine signaling via the JAK-STAT (signal transducers and activators of transcription) pathway. Genetic studies have identified somatic JAK2 V617F mutations and other mutant alleles that activate JAK-STAT signaling in most patients with myeloproliferative neoplasms (MPNs). As a result, JAK inhibitors have been developed to treat various malignancies and have been shown to be efficacious in both preclinical and clinical settings. However, available ATP-competitive JAK (type I) inhibitors are associated with dose-dependent toxicities, and do not yet reduce disease burden in MPN patients. Recent studies suggest that genetic and epigenetic mechanisms can cause insensitivity to type I JAK inhibitors. Novel therapies include the development of type II JAK inhibitors and the use of alternative strategies to abrogate JAK-STAT signaling, perhaps with histone deacetylase (HDAC) and heat shock protein 90 (HSP90) inhibitors. These innovative therapies may translate to treatment of other diseases that are dependent on JAK signaling, including B-precursor acute lymphoblastic leukemia (B-ALL). © 2012 Elsevier Ltd. All rights reserved.
Keywords: signal transduction; myeloproliferative disorders; unclassified drug; histone deacetylase inhibitor; janus kinase 2; lestaurtinib; review; placebo; diarrhea; drug efficacy; nonhuman; side effect; animals; apoptosis; anemia; gastrointestinal symptom; nausea; thrombocytopenia; peripheral neuropathy; enzyme activity; acute lymphoblastic leukemia; dizziness; protein kinase inhibitors; enzyme phosphorylation; drug mechanism; epigenetics; thrombosis; heat shock protein 90 inhibitor; tanespimycin; nausea and vomiting; leukocytosis; panobinostat; myeloproliferative neoplasm; thrombocytosis; 5 (2,4 dihydroxy 5 isopropylphenyl) 4 (4 morpholinomethylphenyl) 3 isoxazolecarboxylic acid ethylamide; n tert butyl 3 [5 methyl 2 [4 (4 methyl 1 piperazinyl)phenylamino] 4 pyrimidinylamino]benzenesulfonamide; stat protein; phase 2 clinical trial (topic); phase 3 clinical trial (topic); phase 1 clinical trial (topic); givinostat; janus kinase 2 inhibitor; janus kinases; n benzyl 2 cyano 3 (3,4 dihydroxyphenyl)acrylamide; 5 chloro n2 [1 (5 fluoro 2 pyrimidinyl)ethyl] n4 (5 methyl 1h pyrazol 3 yl) 2,4 pyrimidinediamine; bms 911543; gandotinib; momelotinib; n tert butyl 3 [5 methyl 2 [4 [2 (1 pyrrolidinyl)ethoxy]phenylamino] 4 pyrimidinylamino]benzenesulfonamide; ns 018; pacritinib; ruxolitinib; tofacitinib
Journal Title: Trends in Pharmacological Sciences
Volume: 33
Issue: 11
ISSN: 0165-6147
Publisher: Cell Press  
Date Published: 2012-11-01
Start Page: 574
End Page: 582
Language: English
DOI: 10.1016/j.tips.2012.08.005
PROVIDER: scopus
PUBMED: 22995223
DOI/URL:
Notes: --- - "Export Date: 3 December 2012" - "CODEN: TPHSD" - "Source: Scopus"
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MSK Authors
  1. Ross Levine
    489 Levine