Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 77, Issue 5, Pages 301-308Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1747-0285.2011.01091.x
Keywords
chemical shift changes; isoindolinones; MDM2; NMR; p53; small-molecule inhibitors
Funding
- Wellcome Trust
- EPSRC
- Cancer Research UK
- Medical Research Council [G1000758, G0700053, G1000758B, G0600698B] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10212] Funding Source: researchfish
- MRC [G0700053] Funding Source: UKRI
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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.
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