Efficacy of TG101348, a Selective JAK2 Inhibitor, in Treatment of a Murine Model of JAK2V617F-Induced Polycythemia Vera

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

Research output: Contribution to journalArticle

268 Scopus citations

Abstract

We report that TG101348, a selective small-molecule inhibitor of JAK2 with an in vitro IC50 of ∼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.

Original languageEnglish (US)
Pages (from-to)311-320
Number of pages10
JournalCancer cell
Volume13
Issue number4
DOIs
StatePublished - Apr 8 2008

Keywords

  • CELLCYCLE
  • CHEMBIO

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Wernig, G., Kharas, M. G., Okabe, R., Moore, S. A., Leeman, D. S., Cullen, D. E., Gozo, M., McDowell, E. P., Levine, R. L., Doukas, J., Mak, C. C., Noronha, G., Martin, M., Ko, Y. D., Lee, B. H., Soll, R. M., Tefferi, A., Hood, J. D., & Gilliland, D. G. (2008). Efficacy of TG101348, a Selective JAK2 Inhibitor, in Treatment of a Murine Model of JAK2V617F-Induced Polycythemia Vera. Cancer cell, 13(4), 311-320. https://doi.org/10.1016/j.ccr.2008.02.009