Design, synthesis, and biological evaluation of quinoxalinone derivatives as potent BRD4 inhibitors

The bromodomain-containing protein 4 (BRD4) has gained growing interest as an effective drug target for the treatment of hepatocellular carcinoma (HCC). Herein, we designed and synthesized a series of quinoxalinone derivatives as BRD4 inhibitors via scaffold hopping. The representative compound X9 showed potent BRD4 inhibitory activity (with IC₅₀ = 82.3 nM), and preferable antiproliferative activity against HepG2 cells (with IC₅₀ = 1.13 ± 0.07 μM), as well as less toxicity against GES-1 cells (with IC₅₀ = 57.24 ± 5.46 μM). Furthermore, compound X9 dose-dependently inhibited colony formation and blocked the migration of HepG2 cells by down-regulating the expression of Snail and MMP-9 while up-regulating the E-cadherin and Occludin. Besides, compound X9 efficiently down-regulated the expression of c-Myc in HepG2 cells, induced Apoptosis, and arrested at G₀/G₁ phase. In total, quinoxalinone was a potential core as BRD4 Inhibitor and compound X9 might be effective for liver Cancer therapy.

Antitumor; BRD4 inhibitors; Quinoxalinone derivatives; c-Myc.