Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein− protein interaction: structure− activity studies leading to improved potency

IR Hardcastle, J Liu, E Valeur, A Watson…

Index: Hardcastle, Ian R.; Liu, Junfeng; Valeur, Eric; Watson, Anna; Ahmed, Shafiq U.; Blackburn, Timothy J.; Bennaceur, Karim; Clegg, William; Drummond, Catherine; Endicott, Jane A.; Golding, Bernard T.; Griffin, Roger J.; Gruber, Jan; Haggerty, Karen; Harrington, Ross W.; Hutton, Claire; Kemp, Stuart; Lu, Xiaohong; McDonnell, James M.; Newell, David R.; Noble, Martin E. M.; Payne, Sara L.; Revill, Charlotte H.; Riedinger, Christiane; Xu, Qing; Lunec, John Journal of Medicinal Chemistry, 2011 , vol. 54, # 5 p. 1233 - 1243

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Citation Number: 68

Abstract

Inhibition of the MDM2-p53 interaction has been shown to produce an antitumor effect, especially in MDM2 amplified tumors. The isoindolinone scaffold has proved to be versatile for the discovery of MDM2-p53 antagonists. Optimization of previously reported inhibitors, for example, NU8231 (7) and NU8165 (49), was guided by MDM2 NMR titrations, which indicated key areas of the binding interaction to be explored. Variation of the 2-N-benzyl ...