Design, synthesis and biological evaluation of dihydroquinoxalinone derivatives as BRD4 inhibitors

• Novel dihydroquinoxalinone BRD4 inhibitors were designed and synthesized.
• Molecular docking was performed.
• Binding activity in BRD4 was determined by AlphaScreen assay.
• Cell viability assay was evaluated in the MV-4-11 cell line.

BRD4 plays a key role in transcriptional regulation. Recent biological and pharmacological studies have demonstrated that bromodomain-containing protein 4 (BRD4) is a viable drug target for cancer treatment. In this study, we synthesized a series of dihydroquinoxalinone derivatives and evaluated their BRD4 inhibitory activities, obtaining compound 5i with IC50 value of 73 nM of binding activity in BRD4(1) and 258 nM of cellular activity in MV-4-11 cancer cell lines. Docking studies were performed to explain the structure-activity relationship. Based on its potent biochemical and anti-proliferative activity, the novel BRD4 inhibitor compound 5i, is a promising lead compound for further investigation.

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