[PDF][PDF] Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera
Cancer cell, 2008•cell.com
We report that TG101348, a selective small-molecule inhibitor of JAK2 with an in vitro IC 50
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 …
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 …
Summary
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.
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