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

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. The interaction between MDM2 and p53 is a major target in anti-cancer drug design. In this paper, we describe the interaction of isoindolinone inhibitors with MDM2, as characterised by NMR spectroscopy. Isoindolinone inhibitors bind specifically to the MDM2 p53 binding-site and exploit the same sub-pockets used by p53, as well as nutlin and spirooxindole inhibitors. [ABSTRACT FROM AUTHOR]