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

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