Browse by author
Lookup NU author(s): Professor Jane Endicott, Stuart Kemp, Dr Lucy Smyth, Dr Eric Valeur, Emeritus Professor Bernard Golding, Professor Roger Griffin, Dr Ian HardcastleORCiD, Professor Martin NobleORCiD
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
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.
Author(s): Riedinger C, Endicott JA, Kemp SJ, Smyth LA, Watson A, Valeur E, Golding BT, Griffin RJ, Hardcastle IR, Noble ME, McDonnell JM
Publication type: Article
Publication status: Published
Journal: Journal of the American Chemical Society
Year: 2008
Volume: 130
Issue: 47
Pages: 16038-16044
Date deposited: 12/05/2010
ISSN (print): 0002-7863
ISSN (electronic): 1520-5126
Publisher: American Chemical Society
URL: http://dx.doi.org/10.1021/ja8062088
DOI: 10.1021/ja8062088
PubMed id: 18959403
Altmetrics provided by Altmetric
