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

作者：Scheper Johanna^*; Guerra Rebollo Marta; Sanclimens Gloria; Moure Alejandra; Masip Isabel; Gonzalez Ruiz Domingo; Rubio Nuria; Crosas Bernat; Meca Cortes Oscar; Loukili Noureddine; Plans Vanessa; Morreale Antonio; Blanco Jeronimo; Ortiz Angel R; Messeguer Angel; Thomson Timothy M

来源：PLos One, 2010, 5(6): e11403.

DOI：10.1371/journal.pone.0011403

Background: pathways that control cell survival under stress, namely RNF8-dependent DNA damage recognition and repair, PCNA-dependent DNA damage tolerance and activation of NF-kappa B 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-kappa B 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.
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.

• 出版日期2010-6-30