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

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Resum

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.

Idioma originalAnglès
Número d’articlee11403
Nombre de pàgines11
RevistaPLoS ONE
Volum5
Número6
DOIs
Estat de la publicacióPublicada - 30 de juny 2010
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