title: Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction.
abstract: A series of 2-N-alkyl-3-aryl-3-alkoxyisoindolinones has been synthesised and evaluated as inhibitors of the MDM2-p53 interaction. The most potent compound, 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (NU8231), exhibited an IC50 of 5.3 +/- 0.9 microM in an ELISA assay, and induced p53-dependent gene transcription in a dose-dependent manner, in the SJSA human sarcoma cell line.
authors.affiliation: Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 7RU, UK. i.r.hardcastle@ncl.ac.uk
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
authors.forename: Shafiq U
authors.initials: SU
authors.lastname: Ahmed
authors.forename: Helen
authors.initials: H
authors.lastname: Atkins
authors.forename: A Hilary
authors.initials: AH
authors.lastname: Calvert
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: Gillian
authors.initials: G
authors.lastname: Farnie
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Sabrina
authors.initials: S
authors.lastname: Guyenne
authors.forename: Claire
authors.initials: C
authors.lastname: Hutton
authors.forename: Per
authors.initials: P
authors.lastname: Källblad
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Kemp
authors.forename: Martin S
authors.initials: MS
authors.lastname: Kitching
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Stefano
authors.initials: S
authors.lastname: Norbedo
authors.forename: Julian S
authors.initials: JS
authors.lastname: Northen
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Reid
authors.forename: K
authors.initials: K
authors.lastname: Saravanan
authors.forename: Henriëtte M G
authors.initials: HM
authors.lastname: Willems
authors.forename: John
authors.initials: J
authors.lastname: Lunec
mesh_terms: D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: C501634:3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one; D007211:Indoles; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2