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.
AuthorsY 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
JournalLeukemia (Leukemia) Vol. 19 Issue 6 Pg. 930-5 (Jun 2005) ISSN: 0887-6924 [Print] England
PMID15815726 (Publication Type: Journal Article)
Chemical References
  • 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
  • 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, genetics, metabolism)
  • Milk Proteins (metabolism)
  • Mutation
  • Phosphorylation (drug effects)
  • Protein Kinase Inhibitors (chemistry, pharmacology)
  • Proto-Oncogene Proteins (antagonists & inhibitors, genetics, metabolism)
  • Quinolines (chemistry, pharmacology)
  • Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
  • STAT5 Transcription Factor
  • Trans-Activators (metabolism)
  • Urea (analogs & derivatives, chemistry, pharmacology)
  • fms-Like Tyrosine Kinase 3

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