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

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.

• Authors: Louise M Kelly, Jin-Chen Yu, Christina L Boulton, Mutiah Apatira, Jason Li, Carol M Sullivan, Ifor Williams, Sonia M Amaral, David P Curley, Nicole Duclos, Donna Neuberg, Robert M Scarborough, Anjali Pandey, Stanley Hollenbach, Keith Abe, Nathalie A Lokker, D Gary Gilliland, Neill A Giese
• Journal: Cancer cell (Cancer Cell) Vol. 1 Issue 5 Pg. 421-32 (Jun 2002) ISSN: 1535-6108 [Print] United States
• PMID: 12124172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Bone Marrow Cells (enzymology, pathology)
• Bone Marrow Transplantation
• Enzyme Inhibitors (pharmacology)
• Flow Cytometry
• Humans
• Immunoblotting
• Interleukin-3 (metabolism)
• Leukemia, Myeloid, Acute (drug therapy, enzymology, genetics)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mutation
• Phosphorylation
• Piperazines (pharmacology)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-kit (drug effects, metabolism)
• Quinazolines (pharmacology)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, 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