2. Academic Validation
  3. MDM2-p53 protein-protein interaction inhibitors: a-ring substituted isoindolinones

MDM2-p53 protein-protein interaction inhibitors: a-ring substituted isoindolinones

  • Bioorg Med Chem Lett. 2011 Oct 1;21(19):5916-9. doi: 10.1016/j.bmcl.2011.07.084.
Anna F Watson 1,  Junfeng Liu,  Karim Bennaceur,  Catherine J Drummond,  Jane A Endicott,  Bernard T Golding,  Roger J Griffin,  Karen Haggerty,  Xiaohong Lu,  James M McDonnell,  David R Newell,  Martin E M Noble,  Charlotte H Revill,  Christiane Riedinger,  Qing Xu,  Yan Zhao,  John Lunec,  Ian R Hardcastle
Affiliations

Affiliation

  • 1 Newcastle Cancer Centre at the Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University, Newcastle, NE1 7RU, UK.
PMID: 21875801 DOI: 10.1016/j.bmcl.2011.07.084
Abstract

Structure-activity relationships for the MDM2-p53 inhibitory activity of a series of A-ring substituted 2-N-benzyl-3-(4-chlorophenyl)-3-(1-(hydroxymethyl)cyclopropyl)methoxy)isoindolinones have been investigated, giving rise to compounds with improved potency over their unsubstituted counterparts. Isoindolinone A-ring substitution with a 4-chloro group for the 4-nitrobenzyl, 4-bromobenzyl and 4-cyanobenzyl derivatives (10a-c) and substitution with a 6-tert-butyl group for the 4-nitrobenzyl derivative (10j) were found to confer additional potency. Resolution of the enantiomers of 10a showed that potent MDM2-p53 activity resided in the (-)-enantiomer ((-)-10a; IC(50)=44 ± 6 nM). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compounds 10a and (-)-10a increase p53 protein levels, activate p53-dependent MDM2 and p21 transcription in MDM2 amplified cells, and show improved selectivity for growth inhibition in wild type p53 cell lines over the parent compound.

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