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Molecular Targets for Therapy

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

Leukemia volume 21, pages 1658–1668 (2007)Cite this article

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.

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Acknowledgements

This work was partially supported by research grants from the Myeloproliferative Disorders Foundation, (Chicago, IL, USA) and from TargeGen Inc., (San Diego, CA, USA).

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Authors and Affiliations

  1. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    A Pardanani, T Lasho, C Finke, R Mesa & A Tefferi

  2. Research and Development, TargeGen Inc., San Diego, CA, USA

    J Hood, M B Martin, G Noronha, C C Mak, H Zhu & R Soll

  3. Brigham and Women's Hospital and the Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    R L Levine & D G Gilliland

  4. Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA

    D G Gilliland

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  1. A Pardanani
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  2. J Hood
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  3. T Lasho
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  4. R L Levine
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  5. M B Martin
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  6. G Noronha
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  7. C Finke
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  8. C C Mak
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  9. R Mesa
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  10. H Zhu
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  11. R Soll
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  12. D G Gilliland
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  13. A Tefferi
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Correspondence to A Tefferi.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Pardanani, A., Hood, J., Lasho, T. et al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia 21, 1658–1668 (2007). https://doi.org/10.1038/sj.leu.2404750

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