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.
Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Christiane
C
Riedinger
Martin E
ME
Noble
David J
DJ
Wright
Florian
F
Mulks
Ian R
IR
Hardcastle
Jane A
JA
Endicott
James M
JM
McDonnell
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D054833:Isoindoles / Q000494:pharmacology*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D054833:Isoindoles; D010879:Piperazines; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2