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Understanding Small-Molecule Binding to MDM2: Insights into Structural Effects of Isoindolinone Inhibitors from NMR Spectroscopy

Authors :
Ian R. Hardcastle
Jane A. Endicott
Florian F. Mulks
James M. McDonnell
David J. Wright
Christiane Riedinger
Martin E.M. Noble
Source :
Chemical Biology & Drug Design. 77:301-308
Publication Year :
2011
Publisher :
Wiley, 2011.

Abstract

The interaction between murine double minute (MDM2) and p53 is a major target in anticancer drug design. Several potent compound series, including the nutlins and spirooxindoles, have previously been established as high-affinity antagonists of MDM2. In this paper, we describe the interaction of isoindolinone inhibitors with MDM2, as characterized by nuclear magnetic resonance spectroscopy. Isoindolinone inhibitors bind specifically to the MDM2 p53 binding site and exploit all sub-pockets used by p53, nutlins and spirooxindoles. Furthermore, isoindolinones bind with low micromolar to high nanomolar affinities, with the best compound approaching the potency of nutlin-3.

Details

ISSN :
17470277
Volume :
77
Database :
OpenAIRE
Journal :
Chemical Biology & Drug Design
Accession number :
edsair.doi...........d0fcd259acef93ed1bb071ab6811686c