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

被引：311

作者：

Werning, Gerlinde ^{[1
]}

Kharas, Michael G. ^{[1
]}

Okabe, Rachel ^{[1
]}

Moore, Sandra A. ^{[1
]}

Leeman, Dena S. ^{[1
]}

Cullen, Dana E. ^{[1
]}

Gozo, Maricel ^{[1
]}

McDowell, Elizabeth P. ^{[1
]}

Levine, Ross L. ^{[1
,3
]}

Doukas, John ^{[5
]}

Mak, Chi Ching ^{[5
]}

Noronha, Glenn ^{[5
]}

Martin, Michael ^{[5
]}

Ko, Yon D. ^{[6
]}

Lee, Benjamin H. ^{[1
]}

Soll, Richard M. ^{[5
]}

Tefferi, Ayalew ^{[7
]}

Hood, John D. ^{[5
]}

Gilliland, D. Gary ^{[1
,2
,4
]}

机构：

[1] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA

[4] Howard Hughes Med Inst, Boston, MA 02115 USA

[5] TargeGen Inc, San Diego, CA 92121 USA

[6] Johanniter KH, Div Hematol, D-0228 Bonn, Germany

[7] Mayo Clin, Dept Med, Rochester, MN 55905 USA

来源：

CANCER CELL | 2008年 / 13卷 / 04期

关键词：

D O I：

10.1016/j.ccr.2008.02.009

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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

引用

页码：311 / 320

页数：10

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