title: Protein-protein interaction antagonists as novel inhibitors of non-canonical polyubiquitylation.
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-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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cell Biology, Institute for Molecular Biology (IBMB-CSIC), Barcelona, Spain.
authors.forename: Johanna
authors.initials: J
authors.lastname: Scheper
authors.forename: Marta
authors.initials: M
authors.lastname: Guerra-Rebollo
authors.forename: Glòria
authors.initials: G
authors.lastname: Sanclimens
authors.forename: Alejandra
authors.initials: A
authors.lastname: Moure
authors.forename: Isabel
authors.initials: I
authors.lastname: Masip
authors.forename: Domingo
authors.initials: D
authors.lastname: González-Ruiz
authors.forename: Nuria
authors.initials: N
authors.lastname: Rubio
authors.forename: Bernat
authors.initials: B
authors.lastname: Crosas
authors.forename: Oscar
authors.initials: O
authors.lastname: Meca-Cortés
authors.forename: Noureddine
authors.initials: N
authors.lastname: Loukili
authors.forename: Vanessa
authors.initials: V
authors.lastname: Plans
authors.forename: Antonio
authors.initials: A
authors.lastname: Morreale
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Blanco
authors.forename: Angel R
authors.initials: AR
authors.lastname: Ortiz
authors.forename: Angel
authors.initials: A
authors.lastname: Messeguer
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Thomson
mesh_terms: D000818:Animals; D002384:Catalysis; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D023421:Models, Animal; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D016328:NF-kappa B; D011506:Proteins