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

• Published in: Clinical cancer research Vol. 13; no. 15; pp. 4575 - 4582
• Main Authors: KIYOI, Hitoshi, SHIOTSU, Yukimasa, NAOE, Tomoki, OZEKI, Kazutaka, YAMAJI, Satomi, KOSUGI, Hiroshi, UMEHARA, Hiroshi, SHIMIZU, Makiko, ARAI, Hitoshi, ISHII, Kenichi, AKINAGA, Shiro
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2007
• Subjects: Administration, Oral; Animals; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Blotting, Western; Cell Proliferation - drug effects; Cytarabine - pharmacology; Drug Therapy, Combination; Enzyme Inhibitors - pharmacology; FLT3; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; fms-Like Tyrosine Kinase 3 - genetics; Hematologic and hematopoietic diseases; Humans; inhibitor; leukemia; Leukemia - genetics; Leukemia - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Inbred C3H; Mice, SCID; Mutation - genetics; Pharmacology. Drug treatments; Pyridines - pharmacology; Pyrimidines - pharmacology; Signal Transduction; small molecule; STAT5 Transcription Factor - genetics; Tumor Cells, Cultured; tyrosine kinase; Xenograft Model Antitumor Assays; Cell proliferation; C-Onc gene; Leukemia; Genetics; Fms-like tyrosine kinase 3; Malignant hemopathy; Inhibitor; Mutation; Protooncogene
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0225

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 IC 50 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 G 1 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.