title: Fluorescence polarization assay and inhibitor design for MDM2/p53 interaction.
abstract: MDM2 is an important negative regulator of the tumor suppressor protein p53 which regulates the expression of many genes including MDM2. The delicate balance of this autoregulatory loop is crucial for the maintenance of the genome and control of the cell cycle and apoptosis. MDM2 hyperactivity, due to amplification/overexpression or mutational inactivation of the ARF locus, inhibits the function of wild-type p53 and can lead to the development of a wide variety of cancers. Thus, the development of anti-MDM2 therapies may restore normal p53 function in tumor cells and induce growth suppression and apoptosis. We report here a novel high-throughput fluorescence polarization binding assay and its application in rank ordering small-molecule inhibitors that block the binding of MDM2 to a p53-derived fluorescent peptide.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. rumin.zhang@spcorp.com
authors.forename: Rumin
authors.initials: R
authors.lastname: Zhang
authors.forename: Todd
authors.initials: T
authors.lastname: Mayhood
authors.forename: Philip
authors.initials: P
authors.lastname: Lipari
authors.forename: Yaolin
authors.initials: Y
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: Durkin
authors.forename: Rosalinda
authors.initials: R
authors.lastname: Syto
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gesell
authors.forename: Charles
authors.initials: C
authors.lastname: McNemar
authors.forename: William
authors.initials: W
authors.lastname: Windsor
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D002453:Cell Cycle / Q000502:physiology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005454:Fluorescence Polarization; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2