Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold.
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.
Hardcastle
Ian R
IR
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
Ahmed
Shafiq U
SU
Atkins
Helen
H
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
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*
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