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

Johanna Scheper, Marta Guerra-Rebollo, Glòria Sanclimens, Alejandra Moure, Isabel Masip, Domingo González-Ruiz, Nuria Rubio, Bernat Crosas, Óscar Meca-Cortés, Noureddine Loukili, Vanessa Plans, Antonio Morreale, Jerónimo Blanco, Angel R. Ortiz, Àngel Messeguer, Timothy M. Thomson

Research output: Indexed journal article Articlepeer-review

32 Citations (Scopus)

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-κB 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-κB by TNF-α 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.

Original languageEnglish
Article numbere11403
JournalPLoS ONE
Volume5
Issue number6
DOIs
Publication statusPublished - 2010
Externally publishedYes

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