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Publication Abstract from PubMed

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.

Structure-Based Design of Covalent Siah Inhibitors.,Stebbins JL, Santelli E, Feng Y, De SK, Purves A, Motamedchaboki K, Wu B, Ronai ZA, Liddington RC, Pellecchia M Chem Biol. 2013 Jul 24. pii: S1074-5521(13)00241-X. doi:, 10.1016/j.chembiol.2013.06.008. PMID:23891150^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.