Document Report Card

ID: ALA1137314

Journal: J Med Chem

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

Authors: Hardcastle IR, Ahmed SU, Atkins H, Farnie G, Golding BT, Griffin RJ, Guyenne S, Hutton C, Källblad P, Kemp SJ, Kitching MS, Newell DR, Norbedo S, Northen JS, Reid RJ, Saravanan K, Willems HM, Lunec J.

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.

CiteXplore: 17034127

DOI: 10.1021/jm0601194