Reference - Detail
|Author||Schlierf A, Altmann E, Quancard J, Jefferson AB, Assenberg R, Renatus M, Jones M, Hassiepen U, Schaefer M, Kiffe M, Weiss A, Wiesmann C, Sedrani R, Eder J, Martoglio B.|
|Title||Targeted inhibition of the COP9 signalosome for treatment of cancer.|
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||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|
|Human and Animal Cells||TE-1(RCB1894)|