Correlation Engine 2.0
Clear Search sequence regions

  • Bcl 2 (1)
  • cellular processes (1)
  • cottonseeds (1)
  • CRL1 (3)
  • cul3 protein, human (1)
  • cullin (11)
  • cullin 1 (1)
  • cullin 5 (1)
  • gossypol (7)
  • human (2)
  • human cell (1)
  • MCL 1 (2)
  • NOXA (1)
  • protein human (1)
  • Sun (1)
  • therapies (1)
  • ubiquitin (2)
  • Sizes of these terms reflect their relevance to your search.

    Cullin-RING E3 ligases (CRLs) are the largest family of E3 ubiquitin ligases, responsible for about 20% of the protein degradation by the ubiquitin-proteasome system (UPS). Given their vital roles in multiple cellular processes, and over-activation in many human cancers, CRLs are validated as promising targets for anti-cancer therapies. Activation of CRLs requires cullin neddylation, a process catalysed by three neddylation enzymes. Recently, our group established an AlphaScreen-based in vitro cullin neddylation assay and employed it for high-throughput screening to search for small-molecule inhibitors targeting cullin neddylation. During our pilot screen, gossypol, a natural product extracted from cottonseeds, was identified as one of the most potent neddylation inhibitors of cullin-1 and cullin-5. We further demonstrated that gossypol blocks cullin neddylation by binding to cullin-1/-5 to inactivate CRL1/5 ligase activity, leading to accumulation of MCL-1 and NOXA, the substrates of CRL1 and CRL5, respectively. The combination of gossypol and an MCL-1 inhibitor synergistically enhanced the anti-proliferative effect in multiple human cancer cell lines. Our study unveiled a rational combination of two previously known inhibitors of the Bcl-2 family for enhanced anti-cancer efficacy and identified a novel activity of gossypol as an inhibitor of CRL1 and CRL5 E3s, thus providing a new possibility in the development of novel CRL inhibitors for anti-cancer therapy. © 2021 Yu and Sun.


    Qing Yu, Yi Sun. Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start? Drug design, development and therapy. 2021;15:1-8

    Expand section icon Mesh Tags

    Expand section icon Substances

    PMID: 33442232

    View Full Text