Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase.
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 (IC(50)<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.
Komeno
Y
Y
Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Kurokawa
M
M
Imai
Y
Y
Takeshita
M
M
Matsumura
T
T
Kubo
K
K
Yoshino
T
T
Nishiyama
U
U
Kuwaki
T
T
Kubo
K
K
Osawa
T
T
Ogawa
S
S
Chiba
S
S
Miwa
A
A
Hirai
H
H
D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008894:Milk Proteins / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D051941:fms-Like Tyrosine Kinase 3
D004268:DNA-Binding Proteins; C501587:Ki23819; D008894:Milk Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011804:Quinolines; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014508:Urea; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D048049:Extracellular Signal-Regulated MAP Kinases