Abstract
A high-throughput screen of our compound archive revealed a novel class of dual FMS-like tyrosine kinase 3 (FLT3)/c-KIT inhibitors. With the help of molecular modeling, this class was rapidly optimized for both potency against FLT3 and FLT3/c-KIT and excellent potency in cell-based assays, leading to dose-dependent cell death in acute myelogenous leukemia (AML) patient blast samples. Ultimately, the AML patient blast data defined the preferred target profile as we designed and evaluated a set of FLT3 selective and FLT3/c-KIT dual molecules. Further optimization for pharmacokinetic properties resulted in the selection of the dual FLT3/c-KIT inhibitor, N(3)-(4-(trans-4-morpholinocyclohexyl)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine, VX-322 (compound 37), to move forward to preclinical evaluation.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Drug Design
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Drug Screening Assays, Antitumor
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Humans
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Hydrogen Bonding
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Injections, Intravenous
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Leukemia, Myeloid, Acute / drug therapy
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Leukemia, Myeloid, Acute / pathology*
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Macaca fascicularis
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Mice
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Mice, Inbred BALB C
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Models, Molecular
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Morpholines / chemical synthesis*
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Morpholines / pharmacokinetics
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Morpholines / pharmacology
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Protein Binding
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Proto-Oncogene Proteins c-kit / antagonists & inhibitors*
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Triazoles / chemical synthesis*
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Triazoles / pharmacokinetics
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Triazoles / pharmacology
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
Substances
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Antineoplastic Agents
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Morpholines
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N3-(4-(4-morpholinocyclohexyl)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine
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Triazoles
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Proto-Oncogene Proteins c-kit
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fms-Like Tyrosine Kinase 3