Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction.
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.
Hardcastle
Ian R
IR
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
Ahmed
Shafiq U
SU
Atkins
Helen
H
Calvert
A Hilary
AH
Curtin
Nicola J
NJ
Farnie
Gillian
G
Golding
Bernard T
BT
Griffin
Roger J
RJ
Guyenne
Sabrina
S
Hutton
Claire
C
Källblad
Per
P
Kemp
Stuart J
SJ
Kitching
Martin S
MS
Newell
David R
DR
Norbedo
Stefano
S
Northen
Julian S
JS
Reid
Rebecca J
RJ
Saravanan
K
K
Willems
Henriëtte M G
HM
Lunec
John
J
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
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