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Analysis of Chemical Shift Changes Reveals the Binding Modes of Isoindolinone Inhibitors of the MDM2-p53 Interaction

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


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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.

Publication metadata

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


DOI: 10.1021/ja8062088

PubMed id: 18959403


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