Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera.

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.
Authors	Gerlinde Wernig, Michael G Kharas, Rachel Okabe, Sandra A Moore, Dena S Leeman, Dana E Cullen, Maricel Gozo, Elizabeth P McDowell, Ross L Levine, John Doukas, Chi Ching Mak, Glenn Noronha, Michael Martin, Yon D Ko, Benjamin H Lee, Richard M Soll, Ayalew Tefferi, John D Hood, D Gary Gilliland
Journal	Cancer cell (Cancer Cell) Vol. 13 Issue 4 Pg. 311-20 (Apr 2008) ISSN: 1878-3686 [Electronic] United States
PMID	18394554 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Protein Kinase Inhibitors Pyrrolidines Sulfonamides Phenylalanine fedratinib Janus Kinase 2 Valine
Topics	Amino Acid Substitution Animals Bone Marrow Transplantation Cell Line, Tumor Colony-Forming Units Assay Disease Models, Animal Endpoint Determination Flow Cytometry Hematopoietic System (cytology, drug effects) Humans Janus Kinase 2 (antagonists & inhibitors, genetics, metabolism) Mice Mice, Inbred C57BL Phenylalanine (genetics) Polycythemia Vera (drug therapy, enzymology) Protein Kinase Inhibitors (pharmacokinetics, pharmacology, therapeutic use) Pyrrolidines (pharmacokinetics, therapeutic use) Signal Transduction (drug effects) Sulfonamides (pharmacokinetics, therapeutic use) Survival Rate Treatment Outcome Valine (genetics)

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