Journal Article

Protein-Protein Interaction Antagonists as Novel Inhibitors of Non-Canonical Polyubiquitylation

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

2010

Overview

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-kappaB 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. 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-kappaB by TNF-alpha and sensitize tumor cells to chemotherapeutic agents. One of these compounds significantly inhibited invasiveness, clonogenicity and tumor growth of prostate cancer cells. 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: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Animals / Antagonists / Biological effects / Catalysis / Cell Biology/Cell Signaling / Cell survival / Cells (Biology) / Chemical Biology / Chemical compounds / Chemotherapy / Combinatorial analysis / Damage tolerance / Deoxyribonucleic acid / DNA / DNA damage / DNA repair / Drug resistance / Enzymatic activity / HeLa Cells / Humans / In vivo methods and tests / Inhibitors / Invasiveness / Kinases / Lysine / Mammalian cells / Medical screening / Mice / Models, Animal / Models, Molecular / NF-kappa B - metabolism / NF-κB protein / Oncology / Pharmacology / Proliferating cell nuclear antigen / Prostate cancer / Protein Binding / Protein interaction / Protein-protein interactions / Proteins / Proteins - metabolism / Saccharomyces cerevisiae / Stem cells / Stress management / Tagging / Therapeutic applications / Tumor cells / Tumor necrosis factor-TNF / Tumor necrosis factor-α / Ubiquitin / Ubiquitination