title: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development L.L.C., 665 Stockton Drive, Exton, Pennsylvania 19341, USA. bgrasber@prdus.jnj.com
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Grasberger
authors.forename: Tianbao
authors.initials: T
authors.lastname: Lu
authors.forename: Carsten
authors.initials: C
authors.lastname: Schubert
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Parks
authors.forename: Theodore E
authors.initials: TE
authors.lastname: Carver
authors.forename: Holly K
authors.initials: HK
authors.lastname: Koblish
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Louis V
authors.initials: LV
authors.lastname: LaFrance
authors.forename: Karen L
authors.initials: KL
authors.lastname: Milkiewicz
authors.forename: Raul R
authors.initials: RR
authors.lastname: Calvo
authors.forename: Diane
authors.initials: D
authors.lastname: Maguire
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lattanze
authors.forename: Carol F
authors.initials: CF
authors.lastname: Franks
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Zhao
authors.forename: Kannan
authors.initials: K
authors.lastname: Ramachandren
authors.forename: Gwendolyn R
authors.initials: GR
authors.lastname: Bylebyl
authors.forename: Marie
authors.initials: M
authors.lastname: Zhang
authors.forename: Carl L
authors.initials: CL
authors.lastname: Manthey
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Petrella
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pantoliano
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Deckman
authors.forename: John C
authors.initials: JC
authors.lastname: Spurlino
authors.forename: Anna C
authors.initials: AC
authors.lastname: Maroney
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Tomczuk
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Molloy
authors.forename: Roger F
authors.initials: RF
authors.lastname: Bone
mesh_terms: D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051736:Proto-Oncogene Proteins c-mdm2; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000096:biosynthesis
chemical_list: D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D001569:Benzodiazepines; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2