Altmann, Eva, Schlierf, Anita, Jefferson, AB, Renatus, Martin, Jones, Matthew, Hassiepen, Ulrich, Assenberg, Rene, Schaefer, Michael, Quancard, Jean, Kiffe, Michael, Weiss, Andreas, Wiesmann, Christian, Sedrani, Richard, Eder, Joerg and Martoglio, Bruno (2016) A first-in-class small molecule inhibitor of the COP9 signalosome subunit 5 for the treatment of cancer. Nature communications, 7. pp. 13166-13175. ISSN 2041-1723

Abstract

The COP9 signalosome (CSN) is the platform for assembly and disassembly of
cullin-RING E3 ubiquitin ligases (CRL), which comprise the largest enzyme
family of the ubiquitin proteasome system (UPS) in humans1-4 . Over 200 CRL
complexes are implicated in the regulation of almost all cellular processes
including cell cycle progression, transcription, and apoptosis5, and aberrant
CRL activity is frequently associated with cancer6-8. Since CSN functions as the
protease which cleaves the ubiquitin-like protein Nedd8 from CRLs and thereby
initiates their remodelling, inhibitors of the catalytic subunit CSN59 may have
therapeutic potential for the treatment of tumours10,11. Here we present CSN5i-
3, a potent, selective and orally available small molecule inhibitor of CSN5. The
compound traps CRLs in the neddylated, active state leading to the autoinactivation
of a subset of CRLs, e.g. SCFSkp2, by inducing the degradation of
their substrate recognition module (SRM). As a result, the corresponding CRL
substrates are stabilized, e.g. tumour suppressors p21 and p27. Surprisingly,
we also found CRLs, e.g. SCFβTrCP, whose SRMs are not degraded upon CSN5
inhibition, and their substrates remain unaffected. CSN5i-3 differentially
affected tumour cell lines and suppressed growth of a human xenograft in
mice. Our results provide insights into how CSN regulates CRLs and suggest
that CSN5 inhibition has therapeutic potential for the treatment of cancer.

Item Type:	Article
Keywords:	COPS5/JAB1, cullin E3 ubiquitin ligase, metalloprotease, tumour suppressor, ubiquitin proteasome system
Date Deposited:	15 Dec 2016 00:45
Last Modified:	15 Dec 2016 00:45
URI:	https://oak.novartis.com/id/eprint/27896