期刊
CANCER CELL
卷 13, 期 4, 页码 311-320出版社
CELL PRESS
DOI: 10.1016/j.ccr.2008.02.009
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资金
- Howard Hughes Medical Institute Funding Source: Medline
- NCI NIH HHS [CA66996, P01 CA066996, CA105423] Funding Source: Medline
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.
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