Understanding small-molecule binding to MDM2: Insights into structural effects of isoindolinone inhibitors from NMR spectroscopy (2011)

Author(s): Riedinger C, Noble ME, Wright DJ, Mulks F, Hardcastle I, Endicott JA, McDonnell JM

    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.

      • Date: 01-03-2011
      • Journal: Chemical Biology and Drug Design
      • Volume: 77
      • Issue: 5
      • Pages: 301-308
      • Publisher: Wiley-Blackwell Publishing, Inc.
      • Publication type: Article
      • Bibliographic status: Published

      Professor Jane Endicott
      Prof of Cancer Structural Biology

      Dr Ian Hardcastle
      Reader in Medicinal Chemistry

      Professor Martin Noble
      Prof of Biom Struct & Anticanc Drug Des