Analysis of chemical shift changes reveals the binding modes of isoindolinone inhibitors of the MDM2-p53 interaction.
In this study we present a method for defining the binding modes of a set of structurally related isoindolinone inhibitors of the MDM2-p53 interaction. This approach derives the location and orientation of isoindolinone binding, based on an analysis of the patterns of magnitude and direction of chemical shift perturbations for a series of inhibitors of the MDM2-p53 interaction. The MDM2-p53 complex is an attractive target for therapeutic intervention in cancer cells with intact tumor suppressor p53, as it offers the possibility of releasing p53 by blocking the MDM2-p53 binding site with a small molecule antagonist to promote apoptosis. Isoindolinones are a novel class of MDM2-antagonists of moderate affinity, which still require the development of more potent candidates for clinical applications. As the applicability of conventional structural methods to this system is limited by a number of fundamental factors, the exploitation of the information contained in chemical shift perturbations has offered a useful route to obtaining structural information to guide the development of more potent compounds. For a set of 12 structurally related isoindolinones, the data suggests 4 different orientations of binding, caused by subtle changes in the chemical structure of the inhibitors.
Riedinger
Christiane
C
Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Endicott
Jane A
JA
Kemp
Stuart J
SJ
Smyth
Lynette A
LA
Watson
Anna
A
Valeur
Eric
E
Golding
Bernard T
BT
Griffin
Roger J
RJ
Hardcastle
Ian R
IR
Noble
Martin E
ME
McDonnell
James M
JM
D001665:Binding Sites; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D007211:Indoles; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2