AZD5153, a bivalent BRD4 inhibitor, inhibits hepatocellular cancer growth by modulating the HCC transcriptome through repression of critical oncogenes through dissociation of BRD4 from the enhancer/promoter regions of critical genes

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related death worldwide because of late stage detection when curative therapy is not available. The bromodomain and extraterminal (BET) protein BRD4 activates gene expression by interacting with histone H3K27-acetylated (H3K27Ac) chromatin. AZD5153 is an orally bioavailable, potent, bivalent BRD4 inhibitor, currently undergoing clinical trials in lymphoma and ovarian cancer patients. Here, we studied therapeutic potential of AZD5153 against HCC and elucidated the underlying mechanism. In conclusion, our results in preclinical models indicate that the combined effect of AZD5153 could be a novel targeted therapy for HCC and provides rationale for clinical trials of an AZD5153-FK866 combination as an effective and attractive strategy to treat this deadly disease. Overall design: Identifying chromosomal targets of BDR4 and H3K27Ac that are disrupted by the AZD5153 treatment