Document Type

Journal Article

Department/Unit

Department of Chemistry

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.

Publication Year

2015

Journal Title

Chemical Science

Volume number

6

Issue number

10

Publisher

Royal Society of Chemistry

First Page (page number)

5400

Last Page (page number)

5408

Referreed

1

DOI

10.1039/C5SC02321A

ISSN (print)

20416520

Link to Publisher’s Edition

http://dx.doi.org/10.1039/C5SC02321A

Additional Files

JA-5034-28944_publisher_suppl.pdf (806 kB)

Included in

Chemistry Commons

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