title: Targeted inhibition of the COP9 signalosome for treatment of cancer.
abstract: 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.
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Anita
authors: A
authors: Schlierf
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Eva
authors: E
authors: Altmann
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Jean
authors: J
authors: Quancard
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Anne B
authors: AB
authors: Jefferson
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: René
authors: R
authors: Assenberg
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Martin
authors: M
authors: Renatus
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Matthew
authors: M
authors: Jones
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Ulrich
authors: U
authors: Hassiepen
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Michael
authors: M
authors: Schaefer
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Michael
authors: M
authors: Kiffe
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Andreas
authors: A
authors: Weiss
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Christian
authors: C
authors: Wiesmann
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Richard
authors: R
authors: Sedrani
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Jörg
authors: J
authors: Eder
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors: Bruno
authors: B
authors: Martoglio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis / Q000494:pharmacology*; D000075686:COP9 Signalosome Complex / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D000075687:NEDD8 Protein / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D059748:Proteolysis / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D000074084:THP-1 Cells; D047368:Tumor Burden / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011720:Pyrazoles; C584471:CULL-RING ligase, human; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex