Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein-Protein Interaction: Structure-Activity Studies Leading to Improved Potency

Hardcastle, IR, Liu, J, Valeur, E, Watson, A, Ahmed, Shafiq, Blackburn, TJ, Bennaceur, K, Clegg, W, Drummond, C, Endicott, JA, Golding, BT, Griffin, RJ, Gruber, J, Haggerty, K, Harrington, RW, Hutton, C, Kemp, S, Lu, X, McDonnell, JM, Newell, DR, Noble, ME, Payne, SL, Revill, CH, Riedinger, C, Xu, Q and Lunec, J (2011) Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein-Protein Interaction: Structure-Activity Studies Leading to Improved Potency. J Med Chem, 54 (5). pp. 1233-43.

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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 and 3-alkoxy substituents resulted in the identification of 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (74) as a potent MDM2-p53 inhibitor (IC(50) = 0.23 ± 0.01 μM). Resolution of the enantiomers of 74 showed that potent MDM2-p53 activity primarily resided with the (+)-R-enantiomer (74a; IC(50) = 0.17 ± 0.02 μM). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compound 74a activates p53, MDM2, and p21 transcription in MDM2 amplified cells and shows moderate selectivity for wild-type p53 cell lines in growth inhibition assays.

Item Type: Article
Subjects: Sciences
Divisions: Faculty of Applied Sciences
Faculty of Applied Sciences > Department of Pharmacy Health and Wellbeing
Health Sciences and Wellbeing Beacon
Depositing User: Paula Normington
Date Deposited: 16 Feb 2016 12:07
Last Modified: 16 Feb 2016 12:07
URI: http://sure.sunderland.ac.uk/id/eprint/6010

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