What question did this study set out to answer?

To identify and characterize small-molecule antagonists that disrupt the HDM2-p53 interaction and restore p53 tumor-suppressor activity in cancer cells.

February 1, 2005Journal of Medicinal ChemistryOpen Access

Discovery and Cocrystal Structure of Benzodiazepinedione HDM2 Antagonists That Activate p53 in Cells

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Authors

BGBruce GrasbergerJanssen (United States)TLTianbao LuJohnson & Johnson (United States)CSCarsten J. SchubertETH Zurich

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Implication

Biochemical analysis demonstrates inhibition of HDM2 by benzodiazepinediones in tumor cells, indicating a novel strategy to reactivate p53.

Key Points

To identify and characterize small-molecule antagonists that disrupt the HDM2-p53 interaction and restore p53 tumor-suppressor activity in cancer cells.
Screened chemical libraries using a miniaturized thermal denaturation assay to identify HDM2-p53 interaction antagonists.
Resolved the X-ray cocrystal structure of optimized benzodiazepinedione compounds bound to HDM2.
Assessed p53 target gene transcription and cell proliferation in tumor cell lines expressing wild-type p53.
Identified a novel series of benzodiazepinediones that act as alpha-helix mimetics targeting HDM2.
Optimized antagonists effectively upregulated the transcription of p53 target genes.
Compound treatment decreased the proliferation of tumor cells expressing wild-type p53.

Cite This Study

Grasberger et al. (2005) studied this question.

synapsesocial.com/papers/6a70a5c4a528af2d65c3a85c https://doi.org/10.1021/jm049137g

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Implication

Biochemical analysis demonstrates inhibition of HDM2 by benzodiazepinediones in tumor cells, indicating a novel strategy to reactivate p53.

Discovery and Cocrystal Structure of Benzodiazepinedione HDM2 Antagonists That Activate p53 in Cells

Discussion

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Implication

Key Points

Cite This Study

Discovery and Cocrystal Structure of Benzodiazepinedione HDM2 Antagonists That Activate p53 in Cells

Discussion

Member takes

Implication

Key Points

Cite This Study

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