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 mu M), as well as less toxicity against GES-1 cells (with IC50 = 57.24 +/- 5.46 mu M). 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, com-pound 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.

Automated summary

A series of quinoxalinone derivatives were designed and synthesized as BRD4 inhibitors, among which compound X9 showed potent activity against BRD4 and HepG2 cell proliferation with less toxicity. Furthermore, compound X9 could inhibit colony formation and migration of HepG2 cells, induce apoptosis, and arrest cell cycle progression. In conclusion, quinoxalinone derivatives are potential core structures as BRD4 inhibitors, and compound X9 may be effective for liver cancer therapy.