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J Med Chem. 2005 Feb 24;48(4):909-12.

Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells.

Author information

  • 1Johnson & Johnson Pharmaceutical Research & Development L.L.C., 665 Stockton Drive, Exton, Pennsylvania 19341, USA. bgrasber@prdus.jnj.com

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.

PMID:
15715460
[PubMed - indexed for MEDLINE]
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