title: 1,4-Benzodiazepine-2,5-diones as small molecule antagonists of the HDM2-p53 interaction: discovery and SAR.
abstract: A library of 1,4-benzodiazepine-2,5-diones was screened for binding to the p53-binding domain of HDM2 using Thermofluor, a miniaturized thermal denaturation assay. The hits obtained were shown to bind to HDM2 in the p53-binding pocket using a fluorescence polarization (FP) peptide displacement assay. The potency of the series was optimized, leading to sub-micromolar antagonists of the p53-HDM2 interaction.
authors.affiliation: Johnson and Johnson Pharmaceutical Research and Development, 665 Stockton Drive, Exton, PA 19341, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Parks
authors.forename: Louis V
authors.initials: LV
authors.lastname: Lafrance
authors.forename: Raul R
authors.initials: RR
authors.lastname: Calvo
authors.forename: Karen L
authors.initials: KL
authors.lastname: Milkiewicz
authors.forename: Varsha
authors.initials: V
authors.lastname: Gupta
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lattanze
authors.forename: Kannan
authors.initials: K
authors.lastname: Ramachandren
authors.forename: Theodore E
authors.initials: TE
authors.lastname: Carver
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Petrella
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Diane
authors.initials: D
authors.lastname: Maguire
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Grasberger
authors.forename: Tianbao
authors.initials: T
authors.lastname: Lu
mesh_terms: D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D005454:Fluorescence Polarization; D006801:Humans; D020128:Inhibitory Concentration 50; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
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