Design, synthesis, and biological evaluation of quinoxalinone derivatives as potent BRD4 inhibitors. (15th January 2023)

• Record Type: Journal Article
• Authors: Xu, Kai-Yan; Wang, Xue-Ting; Cheng, Lei; Cui, Qi-Hang; Shi, Jian-Tao; Zhang, Li-Wen; Chen, Shi-Wu
• Is Part Of: Bioorganic & medicinal chemistry. Volume 78(2023)
• Publication Date: 2023-01-15
• Subjects: BRD4 inhibitors -- Quinoxalinone derivatives -- c-Myc -- Antitumor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.117152
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Novel quinoxalinone derivatives as BRD4 inhibitors were designed and synthesized. Compound X9 manifested promising BRD4 inhibitory activity (IC50 = 82.3 nM). Compound X9 exhibited superior anti-proliferative activity to HepG2 cell line. Compound X9 displayed good inhibitory effects on the migration and c-Myc protein in HepG2 cell line. Abstract: 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.