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

• Published in: Journal of medicinal chemistry 2005-02, Vol.48 (4), p.909-912
• Main Authors: Grasberger, Bruce L, Lu, Tianbao, Schubert, Carsten, Parks, Daniel J, Carver, Theodore E, Koblish, Holly K, Cummings, Maxwell D, LaFrance, Louis V, Milkiewicz, Karen L, Calvo, Raul R, Maguire, Diane, Lattanze, Jennifer, Franks, Carol F, Zhao, Shuyuan, Ramachandren, Kannan, Bylebyl, Gwendolyn R, Zhang, Marie, Manthey, Carl L, Petrella, Eugene C, Pantoliano, Michael W, Deckman, Ingrid C, Spurlino, John C, Maroney, Anna C, Tomczuk, Bruce E, Molloy, Christopher J, Bone, Roger F
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Benzodiazepines - chemical synthesis; Benzodiazepines - chemistry; Benzodiazepines - pharmacology; Binding Sites; Biological and medical sciences; Cell Line, Tumor; Combinatorial Chemistry Techniques; Crystallography, X-Ray; General aspects; Humans; Medical sciences; Models, Molecular; Molecular Mimicry; Molecular Structure; Nuclear Proteins - antagonists & inhibitors; Pharmacology. Drug treatments; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2; Stereoisomerism; Structure-Activity Relationship; Tumor Suppressor Protein p53 - agonists; Tumor Suppressor Protein p53 - biosynthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049137g

HDM2 binds to an α-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 α-helix mimetic properties. These optimized molecules increase the transcription of p53 target genes and decrease proliferation of tumor cells expressing wild-type p53.