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

Producció científica: Article en revista indexadaArticleAvaluat per experts

32 Cites (Scopus)

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
RevistaPLoS ONE
Volum5
Número6
DOIs
Estat de la publicacióPublicada - 2010
Publicat externament

Fingerprint

Navegar pels temes de recerca de 'Protein-protein interaction antagonists as novel inhibitors of non-canonical polyubiquitylation'. Junts formen un fingerprint únic.

Com citar-ho