Bromodomain containing protein 4(BRD4),as an epigenetic reader,can specifically bind to the acetyl lysine residues of histones and has emerged as an attractive therapeutic target for various diseases,including cancer,cardiac remodeling and heart failure.Herein,we described the discovery of hit 5 bearing 4-phenylquinazoline skeleton through a high-throughput virtual screen using 2,003,400 compound library(enamine).Then,structure-activity relationship(SAR)study was performed and 47 new 4-phenylquinazoline derivatives toward BRD4 were further designed,synthesized and evaluated,using HTRF assay set up in our lab.Eventually,we identified compound C-34,which possessed better pharmacokinetic and physicochemical properties as well as lower cytotoxicity against NRCF and NRCM cells,compared to the pos-itive control JQ1.Using computer-based molecular docking and cellular thermal shift assay,we further verified that C-34 could target BRD4 at molecular and cellular levels.Furthermore,treatment with C-34 effectively alleviated fibroblast activation in vitro and cardiac fibrosis in vivo,which was correlated with the decreased expression of BRD4 downstream target c-MYC as well as the depressed TGF-β1/Smad2/3 signaling pathway.Taken together,our findings indicate that novel BRD4 inhibitor C-34 tethering a 4-phenylquinazoline scaffold can serve as a lead compound for further development to treat fibrotic cardiovascular disease.

Zhangxu He;Haomiao Jiao;Qi An;Xin Zhang;Dan Zengyangzong;Jiale Xu;Hongmin Liu;Liying Ma;Wen Zhao

State Key Laboratory of Esophageal Cancer Prevention and Treatment,Key Laboratory of Advanced Pharmaceutical Technology,Ministry of Education of China,School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001,China;China Meheco Topfond Pharmaceutical Co.,Zhumadian 463000,China

药学学报（英文版）

[1]Zhangxu He;Haomiao Jiao;Qi An;Xin Zhang;Dan Zengyangzong;Jiale Xu;Hongmin Liu;Liying Ma;Wen Zhao-.Discovery of novel 4-phenylquinazoline-based BRD4 inhibitors for cardiac fibrosis)[J].药学学报（英文版）,2022(01):291-307

phenylquinazoline,enamine,NRCF,NRCM

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