TY - JOUR
T1 - Protein-protein interaction antagonists as novel inhibitors of non-canonical polyubiquitylation
AU - Scheper, Johanna
AU - Guerra-Rebollo, Marta
AU - Sanclimens, Glòria
AU - Moure, Alejandra
AU - Masip, Isabel
AU - González-Ruiz, Domingo
AU - Rubio, Nuria
AU - Crosas, Bernat
AU - Meca-Cortés, Óscar
AU - Loukili, Noureddine
AU - Plans, Vanessa
AU - Morreale, Antonio
AU - Blanco, Jerónimo
AU - Ortiz, Angel R.
AU - Messeguer, Àngel
AU - Thomson, Timothy M.
PY - 2010/6/30
Y1 - 2010/6/30
N2 - 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.
AB - 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.
KW - Nf-kappa-b
KW - Ubiquitin-conjugating enzyme
KW - Prostate-cancer cells
KW - Ring finger protein
KW - Chiral side-chains
KW - Dna-repair
KW - Lysine-63 polyubiquitination
KW - Crystal-structure
KW - Drug-resistance
KW - Activation
UR - http://www.scopus.com/inward/record.url?scp=77955341070&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000279370000028&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1371/journal.pone.0011403
DO - 10.1371/journal.pone.0011403
M3 - Article
C2 - 20613989
AN - SCOPUS:77955341070
SN - 1932-6203
VL - 5
JO - PLoS ONE
JF - PLoS ONE
IS - 6
M1 - e11403
ER -