Abstract
The receptor tyrosine kinase FLT-3 is frequently mutated in acute myeloid leukemia; however, current small molecule inhibitors suffer from limited efficacy in the clinic. Conversion of a FLT-3 inhibitor (quizartinib) into a proteolysis targeting chimera (PROTAC) results in a compound that induces degradation of FLT-3 ITD mutant at low nanomolar concentrations. Furthermore, the PROTAC is capable of inhibiting cell growth more potently than the warhead alone while inhibiting fewer off-target kinases. This enhanced antiproliferative activity occurs, despite a slight reduction in the PROTAC's kinase inhibitory activity, via an increased level of apoptosis induction suggesting nonkinase roles for the FLT-3 ITD protein. Additionally, the PROTAC is capable of inducing FLT-3 ITD degradation in vivo. These results suggest that degradation of FLT-3 ITD may provide a useful method for therapeutic intervention.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Benzothiazoles / pharmacokinetics
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Benzothiazoles / pharmacology
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Benzothiazoles / therapeutic use*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Humans
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Mice, Nude
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Phenylurea Compounds / pharmacokinetics
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Phenylurea Compounds / pharmacology
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Phenylurea Compounds / therapeutic use*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Proteolysis
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Ubiquitin-Protein Ligases / metabolism
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Xenograft Model Antitumor Assays
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
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fms-Like Tyrosine Kinase 3 / metabolism
Substances
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Antineoplastic Agents
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Benzothiazoles
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Phenylurea Compounds
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Protein Kinase Inhibitors
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quizartinib
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Ubiquitin-Protein Ligases
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FLT3 protein, human
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fms-Like Tyrosine Kinase 3