Inhibition of nutlin-resistant HDM2 mutants by stapled peptides

Inhibition of nutlin-resistant HDM2 mutants by stapled peptides
Title:
Inhibition of nutlin-resistant HDM2 mutants by stapled peptides
Other Titles:
PLoS One
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Publication Date:
20 November 2013
Citation:
© 2013 Jia Wei et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Abstract:
Pharmacological modulation of p53 activity is an attractive therapeutic strategy in cancers with wild-type p53. Presently in clinical trials, the small molecule Nutlin-3A competitively binds to HDM2, a key negative regulator of p53 and blocks its activity. We have described resistance mutations in HDM2 that selectively reduce affinity for Nutlin but not p53. In the present communication, we show that stapled peptides targeting the same region of HDM2 as Nutlin are refractory to these mutations, and display reduced discrimination between the wild-type and mutant HDM2s with regards to functional abrogation of interaction with p53. The larger interaction footprint afforded by stapled peptides suggests that this class of ligands may prove comparatively more resilient to acquired resistance in a clinical setting.
License type:
http://creativecommons.org/licenses/by/4.0/
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Description:
ISSN:
1932-6203
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