title: Structure-based design of covalent Siah inhibitors.
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.
authors.affiliation: Signal Transduction Program and Cell Death Program, Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Stebbins
authors.forename: Eugenio
authors.initials: E
authors.lastname: Santelli
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Feng
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.forename: Angela
authors.initials: A
authors.lastname: Purves
authors.forename: Khatereh
authors.initials: K
authors.lastname: Motamedchaboki
authors.forename: Bainan
authors.initials: B
authors.lastname: Wu
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
authors.forename: Robert C
authors.initials: RC
authors.lastname: Liddington
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology; D060066:Protein Interaction Maps / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000098563:Seven in Absentia Proteins
chemical_list: D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D010455:Peptides; D057786:Peptidomimetics; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins
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