Abstract
Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells, murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / pharmacology
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Benzamides / administration & dosage
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Humans
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Janus Kinase 2 / antagonists & inhibitors*
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Janus Kinase 2 / genetics*
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Mice
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Mice, Inbred C57BL
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Molecular Sequence Data
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Mutation
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Myeloproliferative Disorders / drug therapy*
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Myeloproliferative Disorders / genetics
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Myeloproliferative Disorders / metabolism
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Protein Kinase Inhibitors / administration & dosage*
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Protein Kinase Inhibitors / pharmacology
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Pyrimidines / administration & dosage
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Receptors, Thrombopoietin / genetics
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Receptors, Thrombopoietin / metabolism
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Sequence Analysis, RNA
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Signal Transduction / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Benzamides
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Protein Kinase Inhibitors
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Pyrimidines
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Receptors, Thrombopoietin
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MPL protein, human
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N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
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JAK2 protein, human
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Janus Kinase 2