TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations

Leukemia. 2007 Aug;21(8):1658-68. doi: 10.1038/sj.leu.2404750. Epub 2007 May 31.

Abstract

JAK2V617F and MPLW515L/K represent recently identified mutations in myeloproliferative disorders (MPD) that cause dysregulated JAK-STAT signaling, which is implicated in MPD pathogenesis. We developed TG101209, an orally bioavailable small molecule that potently inhibits JAK2 (IC(50)=6 nM), FLT3 (IC(50)=25 nM) and RET (IC(50)=17 nM) kinases, with significantly less activity against other tyrosine kinases including JAK3 (IC(50)=169 nM). TG101209 inhibited growth of Ba/F3 cells expressing JAK2V617F or MPLW515L mutations with an IC(50) of approximately 200 nM. In a human JAK2V617F-expressing acute myeloid leukemia cell line, TG101209-induced cell cycle arrest and apoptosis, and inhibited phosphorylation of JAK2V617F, STAT5 and STAT3. Therapeutic efficacy of TG101209 was demonstrated in a nude mouse model. Furthermore, TG101209 suppressed growth of hematopoietic colonies from primary progenitor cells harboring JAK2V617F or MPL515 mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects*
  • Colony-Forming Units Assay
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Janus Kinase 3 / antagonists & inhibitors
  • Janus Kinase 3 / genetics
  • Janus Kinase 3 / metabolism
  • Mice
  • Mice, SCID
  • Mutation / genetics*
  • Myeloproliferative Disorders / drug therapy*
  • Myeloproliferative Disorders / genetics
  • Myeloproliferative Disorders / metabolism
  • Phosphorylation / drug effects
  • Polycythemia Vera / drug therapy
  • Polycythemia Vera / genetics
  • Polycythemia Vera / metabolism
  • Primary Myelofibrosis / drug therapy
  • Primary Myelofibrosis / genetics
  • Primary Myelofibrosis / metabolism
  • Pyrimidines / pharmacology*
  • Receptors, Thrombopoietin / antagonists & inhibitors*
  • Receptors, Thrombopoietin / genetics
  • Receptors, Thrombopoietin / metabolism
  • STAT Transcription Factors / metabolism
  • Stem Cells / drug effects
  • Sulfonamides / pharmacology*
  • Thrombopoietin / metabolism
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
  • fms-Like Tyrosine Kinase 3 / genetics
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

  • Enzyme Inhibitors
  • Pyrimidines
  • Receptors, Thrombopoietin
  • STAT Transcription Factors
  • Sulfonamides
  • TG101209
  • MPL protein, human
  • Thrombopoietin
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Janus Kinase 2
  • Janus Kinase 3