Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold

…, H Atkins, G Farnie, BT Golding, RJ Griffin…

Index: Hardcastle, Ian R.; Ahmed, Shafiq U.; Atkins, Helen; Farnie, Gillian; Golding, Bernard T.; Griffin, Roger J.; Guyenne, Sabrina; Hutton, Claire; Kaellblad, Per; Kemp, Stuart J.; Kitching, Martin S.; Newell, David R.; Norbedo, Stefano; Northen, Julian S.; Reid, Rebecca J.; Saravanan; Willems, Henriette M. G.; Lunec, John Journal of Medicinal Chemistry, 2006 , vol. 49, # 21 p. 6209 - 6221

Full Text: HTML

Citation Number: 99

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; IC50= 15.9±0.8 μM) and 3-(4-chlorophenyl)-3-(4-hydroxy-3, 5-dimethoxybenzyloxy)-2-propyl-2, 3- ...