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

Animesh D 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, Ayalew Tefferi

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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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Myeloproliferative Disorders
Inhibitory Concentration 50
Phosphotransferases
Mutation
Myeloid Cells
Growth
Cell Cycle Checkpoints
Acute Myeloid Leukemia
Nude Mice
Protein-Tyrosine Kinases
Stem Cells
Phosphorylation
TG101209
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. / Pardanani, Animesh D; 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, Ayalew.

In: Leukemia, Vol. 21, No. 8, 08.2007, p. 1658-1668.

Research output: Contribution to journalArticle

Pardanani, AD, Hood, J, Lasho, T, Levine, RL, Martin, MB, Noronha, G, Finke, C, Mak, CC, Mesa, R, Zhu, H, Soll, R, Gilliland, DG & Tefferi, A 2007, 'TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations', Leukemia, vol. 21, no. 8, pp. 1658-1668. https://doi.org/10.1038/sj.leu.2404750
Pardanani, Animesh D ; 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, Ayalew. / TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. In: Leukemia. 2007 ; Vol. 21, No. 8. pp. 1658-1668.
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