Abstract
Epidermal growth factor receptor (EGF-R) tyrosine kinase is known to be overexpressed in several malignancies and is an important target for anticancer drug design. We constructed a homology model to represent the structure of EGF-R and propose that this model can be used to design potent inhibitors of EGF-R. We used our EGF-R model and a docking procedure to rationally design compounds predicted to bind favorably to EGF-R. This approach led to the successful design of a leflunomide metabolite analogue, which was found to have an IC50 value of 1.7 microM in EGF-R inhibition assays and killed >99% of human breast cancer cells in vitro by triggering apoptosis. The reported studies may provide the basis for the development of a new class of potent and clinically useful anti-breast cancer agents.
MeSH terms
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Aniline Compounds / chemical synthesis
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Aniline Compounds / pharmacology*
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Apoptosis
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / enzymology
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Breast Neoplasms / pathology
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Cell Line
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Cell Survival / drug effects
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology
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ErbB Receptors / antagonists & inhibitors*
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Humans
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Isoxazoles / metabolism
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Isoxazoles / pharmacology
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Leflunomide
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Microscopy, Confocal
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Models, Molecular
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Nitriles / chemical synthesis
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Nitriles / pharmacology*
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Protein Conformation
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Tumor Cells, Cultured
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Tumor Stem Cell Assay
Substances
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Aniline Compounds
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Antineoplastic Agents
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Enzyme Inhibitors
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Isoxazoles
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LFM A12
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Nitriles
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ErbB Receptors
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Leflunomide