title: Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold.
abstract: From a set of weakly potent lead compounds, using in silico screening and small library synthesis, a series of 2-alkyl-3-aryl-3-alkoxyisoindolinones has been identified as inhibitors of the MDM2-p53 interaction. Two of the most potent compounds, 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one (76; IC(50) = 15.9 +/- 0.8 microM) and 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (79; IC(50) = 5.3 +/- 0.9 microM), induced p53-dependent gene transcription, in a dose-dependent manner, in the MDM2 amplified, 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, NE1 7RU, United Kingdom. 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: 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: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C515133:2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one; C501634:3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one; D000970:Antineoplastic Agents; D007211:Indoles; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2