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Protein-protein interaction antagonists as novel inhibitors of non-canonical polyubiquitylation

AuthorsScheper, Johanna ; Guerra-Rebollo, Marta; Sanclimens Pérez de Rozas, Gloria; Moure Fernández, Alejandra ; Masip, Isabel ; González Ruiz, Domingo; Rubio, Nuria; Crosas, Bernat ; Meca-Cortés, Óscar ; Loukili, Noureddine; Plans, Vanessa; Morreale, Antonio ; Blanco, Jerónimo ; Ortiz, Ángel R. ; Messeguer Peypoch, Ángel ; Thomson, Timothy M.
Issue Date30-Jun-2010
PublisherPublic Library of Science
CitationPLoS ONE 5(6): e11403 (2010)
Abstract[Background]: Several pathways that control cell survival under stress, namely RNF8-dependent DNA damage recognition and repair, PCNA-dependent DNA damage tolerance and activation of NF-kB by extrinsic signals, are regulated by the tagging of key proteins with lysine 63-based polyubiquitylated chains, catalyzed by the conserved ubiquitin conjugating heterodimeric enzyme Ubc13-Uev. [Methodology/Principal Findings]: By applying a selection based on in vivo protein-protein interaction assays of compounds from a combinatorial chemical library followed by virtual screening, we have developed small molecules that efficiently antagonize the Ubc13-Uev1 protein-protein interaction, inhibiting the enzymatic activity of the heterodimer. In mammalian cells, they inhibit lysine 63-type polyubiquitylation of PCNA, inhibit activation of NF-kB by TNF-a and sensitize tumor cells to chemotherapeutic agents. One of these compounds significantly inhibited invasiveness, clonogenicity and tumor growth of prostate cancer cells. [Conclusions/Significance]: This is the first development of pharmacological inhibitors of non-canonical polyubiquitylation that show that these compounds produce selective biological effects with potential therapeutic applications.
Publisher version (URL)http://dx.doi.org/10.1371/journal.pone.0011403
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