Targeted inhibition of the COP9 signalosome for treatment of cancer

Nat Commun. 2016 Oct 24;7:13166. doi: 10.1038/ncomms13166.


The COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin-proteasome system in humans. CRLs are implicated in the regulation of numerous cellular processes, including cell cycle progression and apoptosis, and aberrant CRL activity is frequently associated with cancer. Remodelling of CRLs is initiated by CSN-catalysed cleavage of the ubiquitin-like activator NEDD8 from CRLs. Here we describe CSN5i-3, a potent, selective and orally available inhibitor of CSN5, the proteolytic subunit of CSN. The compound traps CRLs in the neddylated state, which leads to inactivation of a subset of CRLs by inducing degradation of their substrate recognition module. CSN5i-3 differentially affects the viability of tumour cell lines and suppresses growth of a human xenograft in mice. Our results provide insights into how CSN regulates CRLs and suggest that CSN5 inhibition has potential for anti-tumour therapy.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Azepines / chemical synthesis
  • Azepines / pharmacology*
  • COP9 Signalosome Complex / antagonists & inhibitors*
  • COP9 Signalosome Complex / genetics
  • COP9 Signalosome Complex / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • HCT116 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Lymphoma, Large-Cell, Anaplastic / drug therapy*
  • Lymphoma, Large-Cell, Anaplastic / genetics
  • Lymphoma, Large-Cell, Anaplastic / metabolism
  • Lymphoma, Large-Cell, Anaplastic / pathology
  • Mice
  • Mice, SCID
  • Molecular Targeted Therapy
  • NEDD8 Protein / genetics
  • NEDD8 Protein / metabolism
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism
  • Protein Processing, Post-Translational
  • Proteolysis / drug effects
  • Pyrazoles / chemical synthesis
  • Pyrazoles / pharmacology*
  • THP-1 Cells
  • Tumor Burden / drug effects
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Azepines
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes
  • NEDD8 Protein
  • NEDD8 protein, human
  • Pyrazoles
  • CULL-RING ligase, human
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases
  • COPS5 protein, human
  • COP9 Signalosome Complex