Abstract
A library of 1,4-benzodiazepine-2,5-diones was screened for binding to the p53-binding domain of HDM2 using Thermofluor, a miniaturized thermal denaturation assay. The hits obtained were shown to bind to HDM2 in the p53-binding pocket using a fluorescence polarization (FP) peptide displacement assay. The potency of the series was optimized, leading to sub-micromolar antagonists of the p53-HDM2 interaction.
MeSH terms
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Benzodiazepines / chemical synthesis*
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Benzodiazepines / pharmacology*
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Binding Sites
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Combinatorial Chemistry Techniques
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Fluorescence Polarization
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Humans
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Inhibitory Concentration 50
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Nuclear Proteins / antagonists & inhibitors
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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 / metabolism*
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Proto-Oncogene Proteins c-mdm2
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Structure-Activity Relationship
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Tumor Suppressor Protein p53 / antagonists & inhibitors
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Nuclear Proteins
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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Benzodiazepines
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2