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A Novel FLT3 Inhibitor FI-700 Selectively Suppresses the Growth of Leukemia Cells with FLT3 Mutations

Authors' Affiliations: ¹ Department of Infectious Diseases, Nagoya University School of Medicine, ² Pharmaceutical Research Center of Kyowa Hakko Kogyo, Shizuoka, Japan; ³ Department of Hematology, Ogaki Municipal Hospital, Ogaki, Japan; and ⁴ Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Requests for reprints: Hitoshi Kiyoi, Department of Infectious Diseases, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan. Phone: 81-52-744-2955; Fax: 81-52-744-2801; E-mail: kiyoi{at}med.nagoya-u.ac.jp.

Purpose: The aim of this study was to evaluate the antileukemia activity of a novel FLT3 kinase inhibitor, FI-700.

Experimental Design: The antileukemia activity of FI-700 was evaluated in human leukemia cell lines, mutant or wild-type (Wt)-FLT3–expressing mouse myeloid precursor cell line, 32D and primary acute myeloid leukemia cells, and in xenograft or syngeneic mouse leukemia models.

Results: FI-700 showed a potent IC₅₀ value against FLT3 kinase at 20 nmol/L in an in vitro kinase assay. FI-700 showed selective growth inhibition against mutant FLT3-expressing leukemia cell lines and primary acute myeloid leukemia cells, whereas it did not affect the FLT3 ligand (FL)–driven growth of Wt-FLT3–expressing cells. These antileukemia activities were induced by the significant dephosphorylations of mutant FLT3 and STAT5, which resulted in G₁ arrest of the cell cycle. Oral administration of FI-700 induced the regression of tumors in a s.c. tumor xenograft model and increased the survival of mice in an i.v. transplanted model. Furthermore, FI-700 treatment eradicated FLT3/ITD-expressing leukemia cells, both in the peripheral blood and in the bone marrow. In this experiment, the depletion of FLT3/ITD-expressing cells by FI-700 was more significant than that of Ara-C, whereas bone marrow suppression by FI-700 was lower than that by Ara-C.

Conclusions: FI-700 is a novel and potent FLT3 inhibitor with promising antileukemia activity.

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