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Issue 10, 2015
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An iridium(iii)-based irreversible protein–protein interaction inhibitor of BRD4 as a potent anticancer agent

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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

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Article information


Submitted
26 Jun 2015
Accepted
30 Jul 2015
First published
30 Jul 2015

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2015,6, 5400-5408
Article type
Edge Article

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

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