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

Cancer Cell. 2008 Apr;13(4):311-20. doi: 10.1016/j.ccr.2008.02.009.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution*
  • Animals
  • Bone Marrow Transplantation
  • Cell Line, Tumor
  • Colony-Forming Units Assay
  • Disease Models, Animal*
  • Endpoint Determination
  • Flow Cytometry
  • Hematopoietic System / cytology
  • Hematopoietic System / drug effects
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / genetics*
  • Janus Kinase 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Phenylalanine / genetics
  • Polycythemia Vera / drug therapy*
  • Polycythemia Vera / enzymology*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrrolidines / pharmacokinetics
  • Pyrrolidines / therapeutic use*
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / therapeutic use*
  • Survival Rate
  • Treatment Outcome
  • Valine / genetics

Substances

  • Protein Kinase Inhibitors
  • Pyrrolidines
  • Sulfonamides
  • Phenylalanine
  • Fedratinib
  • Janus Kinase 2
  • Valine