Targeted inhibition of the COP9 signalosome for treatment of cancer

Anita Schlierf, Eva Altmann (), Jean Quancard, Anne B. Jefferson, René Assenberg, Martin Renatus, Matthew Jones, Ulrich Hassiepen, Michael Schaefer, Michael Kiffe, Andreas Weiss, Christian Wiesmann, Richard Sedrani, Jörg Eder () and Bruno Martoglio
Additional contact information
Anita Schlierf: Novartis Institutes for Biomedical Research, Novartis Pharma AG
Eva Altmann: Novartis Institutes for Biomedical Research, Novartis Pharma AG
Jean Quancard: Novartis Institutes for Biomedical Research, Novartis Pharma AG
Anne B. Jefferson: Novartis Institutes for Biomedical Research, Novartis Pharma AG
René Assenberg: Novartis Institutes for Biomedical Research, Novartis Pharma AG
Martin Renatus: Novartis Institutes for Biomedical Research, Novartis Pharma AG
Matthew Jones: Novartis Institutes for Biomedical Research, Novartis Pharma AG
Ulrich Hassiepen: Novartis Institutes for Biomedical Research, Novartis Pharma AG
Michael Schaefer: Novartis Institutes for Biomedical Research, Novartis Pharma AG
Michael Kiffe: Novartis Institutes for Biomedical Research, Novartis Pharma AG
Andreas Weiss: Novartis Institutes for Biomedical Research, Novartis Pharma AG
Christian Wiesmann: Novartis Institutes for Biomedical Research, Novartis Pharma AG
Richard Sedrani: Novartis Institutes for Biomedical Research, Novartis Pharma AG
Jörg Eder: Novartis Institutes for Biomedical Research, Novartis Pharma AG
Bruno Martoglio: Novartis Institutes for Biomedical Research, Novartis Pharma AG

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13166

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