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

Y Komeno; M Kurokawa; Y Imai; M Takeshita; T Matsumura; K Kubo; T Yoshino; U Nishiyama; T Kuwaki; K Kubo; T Osawa; S Ogawa; S Chiba; A Miwa; H Hirai

doi:10.1038/sj.leu.2403736

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

Leukemia. 2005 Jun;19(6):930-5. doi: 10.1038/sj.leu.2403736.

Authors

Y Komeno¹, M Kurokawa, Y Imai, M Takeshita, T Matsumura, K Kubo, T Yoshino, U Nishiyama, T Kuwaki, K Kubo, T Osawa, S Ogawa, S Chiba, A Miwa, H Hirai

Affiliation

¹ Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.

PMID: 15815726
DOI: 10.1038/sj.leu.2403736

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 (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.

MeSH terms

Acute Disease
Apoptosis / drug effects
Cell Division / drug effects
DNA-Binding Proteins / metabolism
Extracellular Signal-Regulated MAP Kinases / metabolism
HL-60 Cells
Humans
K562 Cells
Leukemia, Myeloid / drug therapy*
Leukemia, Myeloid / genetics
Leukemia, Myeloid / metabolism
Milk Proteins / metabolism
Mutation
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins / metabolism
Quinolines / chemistry
Quinolines / pharmacology*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / genetics*
Receptor Protein-Tyrosine Kinases / metabolism
STAT5 Transcription Factor
Trans-Activators / metabolism
Urea / analogs & derivatives*
Urea / chemistry
Urea / pharmacology*
fms-Like Tyrosine Kinase 3

Substances

DNA-Binding Proteins
Ki23819
Milk Proteins
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Quinolines
STAT5 Transcription Factor
Trans-Activators
Urea
FLT3 protein, human
Receptor Protein-Tyrosine Kinases
fms-Like Tyrosine Kinase 3
Extracellular Signal-Regulated MAP Kinases