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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.

Item Type: Article

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.

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More Information

Depositing User: Paula Normington

Identifiers

Item ID: 6010
Identification Number: https://doi.org/10.1021/jm1011929
URI: http://sure.sunderland.ac.uk/id/eprint/6010

Users with ORCIDS

ORCID for Shafiq Ahmed: ORCID iD orcid.org/0000-0001-8701-6889

Catalogue record

Date Deposited: 16 Feb 2016 12:07
Last Modified: 18 Dec 2019 15:38

Contributors

Author: Shafiq Ahmed ORCID iD
Author: IR Hardcastle
Author: J Liu
Author: E Valeur
Author: A Watson
Author: TJ Blackburn
Author: K Bennaceur
Author: W Clegg
Author: C Drummond
Author: JA Endicott
Author: BT Golding
Author: RJ Griffin
Author: J Gruber
Author: K Haggerty
Author: RW Harrington
Author: C Hutton
Author: S Kemp
Author: X Lu
Author: JM McDonnell
Author: DR Newell
Author: ME Noble
Author: SL Payne
Author: CH Revill
Author: C Riedinger
Author: Q Xu
Author: J Lunec

University Divisions

Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences

Subjects

Sciences

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