Jump to main content
Jump to site search

Issue 10, 2015
Previous Article Next Article

An iridium(III)-based irreversible protein–protein interaction inhibitor of BRD4 as a potent anticancer agent

Author affiliations

Abstract

Bromodomain-containing protein 4 (BRD4) has recently emerged as an attractive epigenetic target for anticancer therapy. In this study, an iridium(III) complex is reported as the first metal-based, irreversible inhibitor of BRD4. Complex 1a is able to antagonize the BRD4-acetylated histone protein–protein interaction (PPI) in vitro, and to bind BRD4 and down-regulate c-myc oncogenic expression in cellulo. Chromatin immunoprecipitation (ChIP) analysis revealed that 1a could modulate the interaction between BRD4 and chromatin in melanoma cells, particular at the MYC promoter. Finally, the complex showed potent activity against melanoma xenografts in an in vivo mouse model. To our knowledge, this is the first report of a Group 9 metal complex inhibiting the PPI of a member of the bromodomain and extraterminal domain (BET) family. We envision that complex 1a may serve as a useful scaffold for the development of more potent epigenetic agents against cancers such as melanoma.

Graphical abstract: An iridium(iii)-based irreversible protein–protein interaction inhibitor of BRD4 as a potent anticancer agent

Back to tab navigation

Supplementary files

Publication details

The article was received on 26 jún. 2015, accepted on 30 júl. 2015 and first published on 30 júl. 2015


Article type: Edge Article
DOI: 10.1039/C5SC02321A
Citation: Chem. Sci., 2015,6, 5400-5408
  • Open access: Creative Commons BY-NC license
  •   Request permissions

    An iridium(III)-based irreversible protein–protein interaction inhibitor of BRD4 as a potent anticancer agent

    H. Zhong, L. Lu, K. Leung, C. C. L. Wong, C. Peng, S. Yan, D. Ma, Z. Cai, H. David Wang and C. Leung, Chem. Sci., 2015, 6, 5400
    DOI: 10.1039/C5SC02321A

    This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material and it is not used for commercial purposes.

    Reproduced material should be attributed as follows:

    • For reproduction of material from NJC:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
    • For reproduction of material from PCCP:
      [Original citation] - Published by the PCCP Owner Societies.
    • For reproduction of material from PPS:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
    • For reproduction of material from all other RSC journals:
      [Original citation] - Published by The Royal Society of Chemistry.

    Information about reproducing material from RSC articles with different licences is available on our Permission Requests page.

Search articles by author

Spotlight

Advertisements