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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.

    Grasberger BL, Lu T, Schubert C, Parks DJ, Carver TE, Koblish HK, Cummings MD, LaFrance LV, Milkiewicz KL, Calvo RR, Maguire D, Lattanze J, Franks CF, Zhao S, Ramachandren K, Bylebyl GR, Zhang M, Manthey CL, Petrella EC, Pantoliano MW, Deckman IC, Spurlino JC, Maroney AC, Tomczuk BE, Molloy CJ, Bone RF.

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

    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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