Abstract
FLT3 (fms-related tyrosine kinase/Flk2/Stk-2) is a receptor tyrosine kinase (RTK) primarily expressed on hematopoietic cells. In blasts from acute myelogenous leukemia (AML) patients, 2 classes of FLT3 activating mutations have been identified: internal tandem duplication (ITD) mutations in the juxtamembrane domain (25%-30% of patients) and point mutations in the kinase domain activation loop (7%-8% of patients). FLT3-ITD mutations are the most common molecular defect identified in AML and have been shown to be an independent prognostic factor for decreased survival. FLT3-ITD is therefore an attractive molecular target for therapy. SU11248 is a recently described selective inhibitor with selectivity for split kinase domain RTKs, including platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and KIT. We show that SU11248 also has potent activity against wild-type FLT3 (FLT3-WT), FLT3-ITD, and FLT3 activation loop (FLT3-Asp835) mutants in phosphorylation assays. SU11248 inhibits FLT3-driven phosphorylation and induces apoptosis in vitro. In addition, SU11248 inhibits FLT3-induced VEGF production. The in vivo efficacy of SU11248 was investigated in 2 FLT3-ITD models: a subcutaneous tumor xenograft model and a bone marrow engraftment model. We show that SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model. Pharmacokinetic and pharmacodynamic analysis in subcutaneous tumors showed that a single administration of an efficacious drug dose potently inhibits FLT3-ITD phosphorylation for up to 16 hours following a single dose. These results suggest that further exploration of SU11248 activity in AML patients is warranted.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acute Disease
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Amino Acid Substitution
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Bone Marrow Transplantation
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Endothelial Growth Factors / biosynthesis
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Female
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Humans
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Indoles / pharmacology*
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Indoles / therapeutic use
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Intercellular Signaling Peptides and Proteins / biosynthesis
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Leukemia, Myeloid / enzymology
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Leukemia, Myeloid / pathology
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Lymphokines / biosynthesis
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Mice
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Mice, Inbred NOD
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Mice, Nude
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Mice, SCID
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Phosphorylation / drug effects
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Point Mutation
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Protein Processing, Post-Translational / drug effects
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / genetics
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Pyrroles / pharmacology*
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Pyrroles / therapeutic use
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / genetics
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Recombinant Fusion Proteins / antagonists & inhibitors
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Signal Transduction / drug effects
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Sunitinib
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Tandem Repeat Sequences
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Transfection
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Tumor Cells, Cultured / enzymology
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Xenograft Model Antitumor Assays
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fms-Like Tyrosine Kinase 3
Substances
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Antineoplastic Agents
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Endothelial Growth Factors
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Enzyme Inhibitors
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Indoles
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Neoplasm Proteins
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Proto-Oncogene Proteins
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Pyrroles
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Recombinant Fusion Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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FLT3 protein, human
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Flt3 protein, mouse
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Receptor Protein-Tyrosine Kinases
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fms-Like Tyrosine Kinase 3
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Sunitinib