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

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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

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Extramedullary Hematopoiesis
Disease Eradication
Polycythemia Vera
Primary Myelofibrosis
Leukocyte Count
Hematocrit
Inhibitory Concentration 50
Signal Transduction
Cell Count
Biomarkers
T-Lymphocytes
Polymerase Chain Reaction
Mutation
Therapeutics
TG101348
In Vitro Techniques

Keywords

  • CELLCYCLE
  • CHEMBIO

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Wernig, G., Kharas, M. G., Okabe, R., Moore, S. A., Leeman, D. S., Cullen, D. E., ... 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

Efficacy of TG101348, a Selective JAK2 Inhibitor, in Treatment of a Murine Model of JAK2V617F-Induced Polycythemia Vera. / Wernig, Gerlinde; Kharas, Michael G.; Okabe, Rachel; Moore, Sandra A.; Leeman, Dena S.; Cullen, Dana E.; Gozo, Maricel; McDowell, Elizabeth P.; Levine, Ross L.; Doukas, John; Mak, Chi Ching; Noronha, Glenn; Martin, Michael; Ko, Yon D.; Lee, Benjamin H.; Soll, Richard M.; Tefferi, Ayalew; Hood, John D.; Gilliland, D. Gary.

In: Cancer Cell, Vol. 13, No. 4, 08.04.2008, p. 311-320.

Research output: Contribution to journalArticle

Wernig, G, Kharas, MG, Okabe, R, Moore, SA, Leeman, DS, Cullen, DE, Gozo, M, McDowell, EP, Levine, RL, Doukas, J, Mak, CC, Noronha, G, Martin, M, Ko, YD, Lee, BH, Soll, RM, Tefferi, A, Hood, JD & Gilliland, DG 2008, 'Efficacy of TG101348, a Selective JAK2 Inhibitor, in Treatment of a Murine Model of JAK2V617F-Induced Polycythemia Vera', Cancer Cell, vol. 13, no. 4, pp. 311-320. https://doi.org/10.1016/j.ccr.2008.02.009
Wernig, Gerlinde ; Kharas, Michael G. ; Okabe, Rachel ; Moore, Sandra A. ; Leeman, Dena S. ; Cullen, Dana E. ; Gozo, Maricel ; McDowell, Elizabeth P. ; Levine, Ross L. ; Doukas, John ; Mak, Chi Ching ; Noronha, Glenn ; Martin, Michael ; Ko, Yon D. ; Lee, Benjamin H. ; Soll, Richard M. ; Tefferi, Ayalew ; Hood, John D. ; Gilliland, D. Gary. / Efficacy of TG101348, a Selective JAK2 Inhibitor, in Treatment of a Murine Model of JAK2V617F-Induced Polycythemia Vera. In: Cancer Cell. 2008 ; Vol. 13, No. 4. pp. 311-320.
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