title: Novel 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists with improved cellular activity.
abstract: The disruption of the p53-Hdm2 protein-protein interaction induces cell growth arrest and apoptosis. We have identified the 1,4-benzodiazepine-2,5-dione scaffold as a suitable template for inhibiting this interaction by binding to the Hdm2 protein. Several compounds have been made with improved potency, solubility, and cell-based activities.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 665 Stockton Drive, Exton, PA 19341, USA. kleonar1@prdus.jnj.com
authors.forename: Kristi
authors.initials: K
authors.lastname: Leonard
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Marugan
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
authors.forename: Raul
authors.initials: R
authors.lastname: Calvo
authors.forename: Joan M
authors.initials: JM
authors.lastname: Gushue
authors.forename: Holly K
authors.initials: HK
authors.lastname: Koblish
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lattanze
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Zhao
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
authors.forename: Anna C
authors.initials: AC
authors.lastname: Maroney
authors.forename: Tianbao
authors.initials: T
authors.lastname: Lu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D001569:Benzodiazepines; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2