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Targeted inhibition of the COP9 signalosome for treatment of cancer

Author

Listed:
  • 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
    Present address: Centers for Therapeutic Innovation, Pfizer Inc., San Francisco, California 94158, USA)

  • René Assenberg

    (Novartis Institutes for Biomedical Research, Novartis Pharma AG
    Present address: Janssen Biologics BV, 2333CB Leiden, The Netherlands)

  • 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
    Present address: Pharma Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland)

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.

Suggested Citation

  • Anita Schlierf & Eva Altmann & Jean Quancard & Anne B. Jefferson & René Assenberg & Martin Renatus & Matthew Jones & Ulrich Hassiepen & Michael Schaefer & Michael Kiffe & Andreas Weiss & Christian Wie, 2016. "Targeted inhibition of the COP9 signalosome for treatment of cancer," Nature Communications, Nature, vol. 7(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13166
    DOI: 10.1038/ncomms13166
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    Cited by:

    1. Namrata Kumar & Arjan F. Theil & Vera Roginskaya & Yasmin Ali & Michael Calderon & Simon C. Watkins & Ryan P. Barnes & Patricia L. Opresko & Alex Pines & Hannes Lans & Wim Vermeulen & Bennett Houten, 2022. "Global and transcription-coupled repair of 8-oxoG is initiated by nucleotide excision repair proteins," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Chrysanthi Kagiou & Jose A. Cisneros & Jakob Farnung & Joanna Liwocha & Fabian Offensperger & Kevin Dong & Ka Yang & Gary Tin & Christina S. Horstmann & Matthias Hinterndorfer & Joao A. Paulo & Natali, 2024. "Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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