Abstract
Two libraries of substituted benzimidazoles were designed using a 'scaffold-hopping' approach based on reported MDM2-p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X-ray structure. Benzimidazole libraries were prepared using an efficient solution-phase approach and screened for inhibition of the MDM2-p53 and MDMX-p53 protein-protein interactions. Key examples showed inhibitory activity against both targets.
Keywords:
drug design; drug discovery; protein-protein interaction; structure-based drug design; virtual screening.
© 2014 John Wiley & Sons A/S.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology*
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Cell Cycle Proteins
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Enzyme-Linked Immunosorbent Assay
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Humans
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Models, Molecular
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Molecular Docking Simulation
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / chemistry
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Nuclear Proteins / metabolism
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Protein Binding / drug effects
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-mdm2 / chemistry
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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Tumor Suppressor Protein p53 / antagonists & inhibitors*
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Tumor Suppressor Protein p53 / chemistry
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Tumor Suppressor Protein p53 / metabolism
Substances
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Benzimidazoles
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Cell Cycle Proteins
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Enzyme Inhibitors
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MDM4 protein, human
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Nuclear Proteins
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Proto-Oncogene Proteins
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Small Molecule Libraries
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TP53 protein, human
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2