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Chem Biol. 2013 Aug 22;20(8):973-82. doi: 10.1016/j.chembiol.2013.06.008. Epub 2013 Jul 25.

Structure-based design of covalent Siah inhibitors.

Author information

1
Signal Transduction Program and Cell Death Program, Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

Abstract

The E3 ubiquitin ligase Siah regulates key cellular events that are central to cancer development and progression. A promising route to Siah inhibition is disrupting its interactions with adaptor proteins. However, typical of protein-protein interactions, traditional unbiased approaches to ligand discovery did not produce viable hits against this target, despite considerable effort and a multitude of approaches. Ultimately, a rational structure-based design strategy was successful for the identification of Siah inhibitors in which peptide binding drives specific covalent bond formation with the target. X-ray crystallography, mass spectrometry, and functional data demonstrate that these peptide mimetics are efficient covalent inhibitors of Siah and antagonize Siah-dependent regulation of Erk and Hif signaling in the cell. The proposed strategy may result useful as a general approach to the design of peptide-based inhibitors of other protein-protein interactions.

PMID:
23891150
PMCID:
PMC3763817
DOI:
10.1016/j.chembiol.2013.06.008
[Indexed for MEDLINE]
Free PMC Article

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