Discovery and Cocrystal Structure of Benzodiazepinedione HDM2 Antagonists that Activate

Journal Article · Fri Dec 31 23:00:00 EST 2004 · J. Med. Chem.

DOI:https://doi.org/10.1021/jm049137g· OSTI ID:913774

Grasberger, B; Lu, T; Schubert, C; Parks, D; Carver, T; Koblish, H; Cummings, M; Lafrance, L; Milkiewicz, K

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.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 913774
• Report Number(s): BNL--78342-2007-JA
• Journal Information: J. Med. Chem., Journal Name: J. Med. Chem. Vol. 48
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CRYSTAL STRUCTURE
GENES
NEOPLASMS
PROLIFERATION
SCREENS
TARGETS
TRANSCRIPTION
TUMOR CELLS
national synchrotron light source