Abstract
We report that TG101348, a selective small-molecule inhibitor of JAK2 with an in vitro IC50 of approximately 3 nM, shows therapeutic efficacy in a murine model of myeloproliferative disease induced by the JAK2V617F mutation. In treated animals, there was a statistically significant reduction in hematocrit and leukocyte count, a dose-dependent reduction/elimination of extramedullary hematopoiesis, and, at least in some instances, evidence for attenuation of myelofibrosis. There were no apparent toxicities and no effect on T cell number. In vivo responses were correlated with surrogate endpoints, including reduction/elimination of JAK2V617F disease burden assessed by quantitative genomic PCR, suppression of endogenous erythroid colony formation, and in vivo inhibition of JAK-STAT signal transduction as assessed by flow cytometric measurement of phosphorylated Stat5.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution*
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Animals
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Bone Marrow Transplantation
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Cell Line, Tumor
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Colony-Forming Units Assay
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Disease Models, Animal*
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Endpoint Determination
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Flow Cytometry
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Hematopoietic System / cytology
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Hematopoietic System / 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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Janus Kinase 2 / metabolism
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Mice
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Mice, Inbred C57BL
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Phenylalanine / genetics
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Polycythemia Vera / drug therapy*
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Polycythemia Vera / enzymology*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / therapeutic use*
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Signal Transduction / drug effects
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Sulfonamides / pharmacokinetics
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Sulfonamides / therapeutic use*
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Survival Rate
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Treatment Outcome
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Valine / genetics
Substances
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Protein Kinase Inhibitors
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Pyrrolidines
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Sulfonamides
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Phenylalanine
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fedratinib
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Janus Kinase 2
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Valine