Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction

MEDI 147

Anna F. Watson, anna.watson@ncl.ac.uk1, Bernard T. Golding1, Roger J. Griffin, r.j.griffin@ncl.ac.uk1, Claire Hutton2, Junfeng Liu2, Xiaohong Lu2, John Lunec2, David R. Newell2, Eric Valeur1, and Ian R. Hardcastle, I.R.Hardcastle@newcastle.ac.uk1. (1) Northern Institute for Cancer Research, School of Natural Sciences - Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU, United Kingdom, (2) Northern Institute for Cancer Research, Paul O'Gorman Building, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom
The p53 tumour suppressor acts as 'the guardian of the genome' playing roles in cell cycle progression and apoptosis. In normal cells p53 activity is regulated by the MDM2 protein via a negative feedback loop. Inhibition of the MDM2-p53 protein-protein complex is expected to reactivate normal p53 pathways in cells over-expressing MDM2, resulting in anti-tumour activity. Previously we have identified small molecule inhibitors of the MDM2-p53 interaction based on an isoindolinone scaffold (NU8348 and NU8349). Further optimisation has resulted in the elucidation of structure-activity relationships for the isoindolinone pharmacophore, and the identification of compounds with improved potency, including NU8354. Resolution of the two enantiomers of NU8354 using chiral HPLC gave NU8354A (IC50= 171 15nM) and NU8354B (IC50= 1.30 0.11μM). The cellular activities of key compounds have been demonstrated with dose-dependent induction of p53 regulated genes in a variety of model systems.

 

General Poster Session
7:00 PM-9:00 PM, Sunday, August 17, 2008 Pennsylvania Convention Center -- Hall C, Poster

Division of Medicinal Chemistry

The 236th ACS National Meeting, Philadelphia, PA, August 17-21, 2008