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Molecular Targets for Therapy

Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase

Leukemia volume 19, pages 930–935 (2005)Cite this article

Abstract

Constitutively active internal tandem duplication (ITD) in the juxtamembrane domain of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase, is the most common molecular defect associated with acute myeloid leukemia. Its presence confers a poor outcome in patients with acute myeloid leukemia who receive conventional chemotherapy. FLT3-ITD has therefore been considered to be an attractive molecular target for a novel therapeutic modality. We describe here the identification and characterization of Ki23819 as a novel FLT3 inhibitor. Ki23819 suppressed proliferation and induced apoptosis of FLT3-ITD-expressing human leukemia cell lines. The growth-inhibitory effect of Ki23819 on MV4-11 cells was superior to that of SU11248, another FLT3 inhibitor (IC50<1 vs 3–10?nM). Ki23819 inhibited the autophosphorylation of FLT3-ITD more efficiently than that of wild-type FLT3. FLT3-ITD-dependent activation of the downstream signaling proteins ERK and STAT5 was also inhibited within similar concentration ranges. Thus, Ki23819 is a potent in vitro inhibitor of FLT3.

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Acknowledgements

We thank Dr O Rosnet for providing FLT3 cDNA and Dr K Mitani for her helpful discussions.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Y Komeno, M Kurokawa, Y Imai, M Takeshita, T Matsumura, T Yoshino, S Ogawa, S Chiba & H Hirai

  2. Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd, Gunma, Japan

    K Kubo, T Yoshino, K Kubo, T Osawa & A Miwa

  3. Pharmaceutical Development Laboratories, Kirin Brewery Co., Ltd, Gunma, Japan

    U Nishiyama & T Kuwaki

  4. Department of Regeneration Medicine for Hematopoiesis, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    S Ogawa

  5. Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan

    S Chiba & H Hirai

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Correspondence to M Kurokawa.

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Komeno, Y., Kurokawa, M., Imai, Y. et al. Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase. Leukemia 19, 930–935 (2005). https://doi.org/10.1038/sj.leu.2403736

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  • DOI: https://doi.org/10.1038/sj.leu.2403736

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