Abstract
Inflammation and cancer, two therapeutic areas historically addressed by separate drug discovery efforts, are now coupled in treatment approaches by a growing understanding of the dynamic molecular dialogues between immune and cancer cells. Agents that target specific compartments of the immune system, therefore, not only bring new disease modifying modalities to inflammatory diseases, but also offer a new avenue to cancer therapy by disrupting immune components of the microenvironment that foster tumor growth, progression, immune evasion, and treatment resistance. McDonough feline sarcoma viral (v-fms) oncogene homolog (FMS) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) are two hematopoietic cell surface receptors that regulate the development and function of macrophages and mast cells, respectively. We disclose a highly specific dual FMS and KIT kinase inhibitor developed from a multifaceted chemical scaffold. As expected, this inhibitor blocks the activation of macrophages, osteoclasts, and mast cells controlled by these two receptors. More importantly, the dual FMS and KIT inhibition profile has translated into a combination of benefits in preclinical disease models of inflammation and cancer.
MeSH terms
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Aminopyridines / chemical synthesis
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Aminopyridines / chemistry
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Aminopyridines / pharmacology*
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Animals
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Cell Survival / drug effects
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Chromatography, Affinity
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Crystallization
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Escherichia coli
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Human Umbilical Vein Endothelial Cells
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Humans
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Indoles
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Inflammation / drug therapy*
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Macrophages / drug effects
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Mast Cells / drug effects
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Models, Molecular*
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Molecular Structure
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Mutation, Missense / genetics
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Neoplasm Metastasis / drug therapy*
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Oncogene Protein gp140(v-fms) / antagonists & inhibitors*
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Oncogene Protein gp140(v-fms) / chemistry
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Oncogene Protein gp140(v-fms) / genetics
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Osteoclasts / drug effects
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Protein Conformation
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-kit / antagonists & inhibitors*
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Proto-Oncogene Proteins c-kit / chemistry
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Proto-Oncogene Proteins c-kit / genetics
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Pyrroles / chemical synthesis
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Sf9 Cells
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Spodoptera
Substances
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5-(1H-pyrrolo(2,3-b)pyridin-3-ylmethyl)-N-((4-(trifluoromethyl)phenyl)methyl)pyridin-2-amine
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7-azaindole dimer
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Aminopyridines
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Indoles
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Oncogene Protein gp140(v-fms)
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Protein Kinase Inhibitors
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Pyrroles
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Proto-Oncogene Proteins c-kit