Abstract
HDM2 binds to an alpha-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, resulting in the discovery of a novel series of benzodiazepinedione antagonists of the HDM2-p53 interaction. The X-ray crystal structure of improved antagonists bound to HDM2 reveals their alpha-helix mimetic properties. These optimized molecules increase the transcription of p53 target genes and decrease proliferation of tumor cells expressing wild-type p53.
MeSH terms
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Benzodiazepines / chemical synthesis*
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Benzodiazepines / chemistry
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Benzodiazepines / pharmacology
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Binding Sites
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Cell Line, Tumor
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Combinatorial Chemistry Techniques
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Crystallography, X-Ray
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Humans
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Models, Molecular
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Molecular Mimicry
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Molecular Structure
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Nuclear Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins c-mdm2
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Stereoisomerism
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Structure-Activity Relationship
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Tumor Suppressor Protein p53 / agonists*
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Tumor Suppressor Protein p53 / biosynthesis
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