An iridium(<scp>iii</scp>)-based irreversible protein–protein interaction inhibitor of BRD4 as a potent anticancer agent

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 <b>1a</b> is able to antagonize the BRD4-acetylated histone protein-protein interaction (PPI) <i>in vitro</i>, and to bind BRD4 and down-regulate c-<i>myc</i> oncogenic expression <i>in cellulo</i>. Chromatin immunoprecipitation (ChIP) analysis revealed that <b>1a</b> 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 <i>in vivo</i> 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 <b>1a</b> may serve as a useful scaffold for the development of more potent epigenetic agents against cancers such as melanoma.