Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera
Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera
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DOI：
10.1016/j.ccr.2008.02.009
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发表时间：
2008-04-01
期刊：
影响因子：
50.3
通讯作者：
Gilliland, D. Gary
中科院分区：
文献类型：
--
作者：
Werning, Gerlinde;Kharas, Michael G.;Gilliland, D. Gary
TG101348是一种选择性JAK2小分子抑制剂，体外IC50值接近3 nM，在JAK2V617F突变诱导的小鼠骨髓增生性疾病模型中显示出治疗效果。在治疗过的动物中，红细胞压积和白细胞计数有统计学意义上的显著减少，髓外造血的剂量依赖性减少/消除，并且，至少在某些情况下，有证据表明骨髓纤维化减弱。无明显毒性作用，对T细胞数量无影响。体内反应与替代终点相关，包括通过定量基因组PCR评估的JAK2V617F疾病负担的减少/消除，内源性红系集落形成的抑制，以及通过磷酸化Stat5的流式细胞术测量评估的jj - stat信号转导的体内抑制。
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.