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

A. Pardanani, J. Hood, T. Lasho, R. L. Levine, M. B. Martin, G. Noronha, C. Finke, C. C. Mak, R. Mesa, H. Zhu, R. Soll, D. G. Gilliland, A. Tefferi

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199 Scopus citations

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 (IC50 = 6 nM), FLT3 (IC50 = 25 nM) and RET (IC50 = 17 nM) kinases, with significantly less activity against other tyrosine kinases including JAK3 (IC50 = 169 nM). TG101209 inhibited growth of Ba/F3 cells expressing JAK2V617F or MPLW515L mutations with an IC50 of ∼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.

Original languageEnglish (US)
Pages (from-to)1658-1668
Number of pages11
JournalLeukemia
Volume21
Issue number8
DOIs
StatePublished - Aug 2007

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ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Pardanani, A., Hood, J., Lasho, T., Levine, R. L., Martin, M. B., Noronha, G., Finke, C., Mak, C. C., Mesa, R., Zhu, H., Soll, R., Gilliland, D. G., & Tefferi, A. (2007). TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia, 21(8), 1658-1668. https://doi.org/10.1038/sj.leu.2404750