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Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera CANCER CELL Werning, G., Kharas, M. G., Okabe, R., Moore, S. A., Leeman, D. S., Cullen, D. E., Gozo, M., McDowell, E. P., Levine, R. L., Doukas, J., Mak, C. C., Noronha, G., Martin, M., Ko, Y. D., Lee, B. H., Soll, R. M., Tefferi, A., Hood, J. D., Gilliland, D. G. 2008; 13 (4): 311-320

Abstract

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

View details for DOI 10.1016/j.ccr.2008.02.009

View details for Web of Science ID 000254817400006

View details for PubMedID 18394554