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

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

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

doi

10.1021/jm049137g

keywords:

subject

Has Abstract

pub_date

2005-02-24 00:00:00

pages

909-12

issue

4

eissn

0022-2623

issn

1520-4804

journal_volume

48

pub_type

杂志文章

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