CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML)

Cancer Cell. 2002 Jun;1(5):421-32. doi: 10.1016/s1535-6108(02)00070-3.

Abstract

Up to 30% of acute myelogenous leukemia (AML) patients harbor an activating internal tandem duplication (ITD) within the juxtamembrane domain of the FLT3 receptor, suggesting that it may be a target for kinase inhibitor therapy. For this purpose we have developed CT53518, a potent antagonist that inhibits FLT3, platelet-derived growth factor receptor (PDGFR), and c-Kit (IC(50) approximately 200 nM), while other tyrosine or serine/threonine kinases were not significantly inhibited. In Ba/F3 cells expressing different FLT3-ITD mutants, CT53518 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC(50) of 10-100 nM. In human FLT3-ITD-positive AML cell lines, CT53518 induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways. Therapeutic efficacy of CT53518 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Bone Marrow Cells / enzymology
  • Bone Marrow Cells / pathology
  • Bone Marrow Transplantation
  • Enzyme Inhibitors / pharmacology*
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Interleukin-3 / metabolism
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation
  • Phosphorylation
  • Piperazines / pharmacology*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-kit / drug effects
  • Proto-Oncogene Proteins c-kit / metabolism
  • Quinazolines / pharmacology*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
  • Tandem Repeat Sequences
  • Transfection
  • Tumor Cells, Cultured / drug effects
  • fms-Like Tyrosine Kinase 3

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Interleukin-3
  • Piperazines
  • Proto-Oncogene Proteins
  • Quinazolines
  • Receptors, Cell Surface
  • tandutinib
  • FLT3 protein, human
  • Flt3 protein, mouse
  • Proto-Oncogene Proteins c-kit
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Platelet-Derived Growth Factor
  • fms-Like Tyrosine Kinase 3