Abstract
An integrated, virtual database screening strategy has led to 7-[anilino(phenyl)methyl]-2-methyl-8-quinolinol (4, NSC 66811) as a novel inhibitor of the murine double minute 2 (MDM2)-p53 interaction. This quinolinol binds to MDM2 with a Ki of 120 nM and activates p53 in cancer cells with a mechanism of action consistent with targeting the MDM2-p53 interaction. It mimics three p53 residues critical in the binding to MDM2 and represents a promising new class of non-peptide inhibitors of the MDM2-p53 interaction.
MeSH terms
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Aniline Compounds / chemistry*
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Aniline Compounds / pharmacology
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology
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Binding Sites
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Binding, Competitive
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Cell Line, Tumor
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Crystallography, X-Ray
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Databases, Factual*
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HCT116 Cells
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Humans
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Hydroxyquinolines / chemistry*
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Hydroxyquinolines / pharmacology
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Models, Molecular
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Molecular Mimicry
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Mutation
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Proto-Oncogene Proteins c-mdm2 / chemistry
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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Stereoisomerism
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Tumor Suppressor Protein p53 / chemistry
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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7-(anilino(phenyl)methyl)-2-methyl-8-quinolinol
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Aniline Compounds
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Antineoplastic Agents
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Hydroxyquinolines
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Tumor Suppressor Protein p53
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2