A novel FLT3 inhibitor FI-700 selectively suppresses the growth of leukemia cells with FLT3 mutations.
OBJECTIVE
The aim of this study was to evaluate the antileukemia activity of a novel FLT3 kinase inhibitor, FI-700.


METHODS
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.
Department of Infectious Diseases, Nagoya University School of Medicine, Japan. kiyoi@med.nagoya-u.ac.jp
Hitoshi
H
Kiyoi
Yukimasa
Y
Shiotsu
Kazutaka
K
Ozeki
Satomi
S
Yamaji
Hiroshi
H
Kosugi
Hiroshi
H
Umehara
Makiko
M
Shimizu
Hitoshi
H
Arai
Kenichi
K
Ishii
Shiro
S
Akinaga
Tomoki
T
Naoe
D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C523780:FI-700; D011725:Pyridines; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D003561:Cytarabine; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3