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

Lookup NU author(s): Professor Martin Noble, Dr Ian Hardcastle, Professor Jane Endicott

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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.


Publication metadata

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

Publication type: Article

Journal: Chemical Biology and Drug Design

Year: 2011

Volume: 77

Issue: 5

Pages: 301-308

Print publication date: 01/03/2011

ISSN (print): 1747-0277

ISSN (electronic): 1747-0285

Publisher: Wiley-Blackwell Publishing, Inc.

URL: http://dx.doi.org/10.1111/j.1747-0285.2011.01091.x

DOI: 10.1111/j.1747-0285.2011.01091.x

PubMed id: 21244642


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