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Understanding small-molecule binding to MDM2: Insights into structural effects of isoindolinone inhibitors from NMR spectroscopy

DOI: 10.1111/j.1747-0285.2011.01091.x DOI Help
PMID: 21244642 PMID Help

Authors: Christiane Riedinger (University of Oxford) , Martin Noble (University of Oxford) , David J. Wright (University of Oxford) , Florian Mulks (University of Oxford) , Ian R. Hardcastle (University of Newcastle) , Jane A. Endicott (University of Oxford) , James M. Mcdonnell (University of Oxford; King's College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemical Biology And Drug Design

State: Published (Approved)
Published: March 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.

Journal Keywords: Chemical Shift Changes;Isoindolinones;Mdm2;Nmr;P53;Small-Molecule Inhibitors

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)