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 cance...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 bearing4-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 positive 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.展开更多
基金supported by National Key Grant from Chinese Ministry of Science and Technology(2016YFA0501800 by Wen Zhao)National Natural Science Foundation of China(81870297 by Wen Zhao+3 种基金81703328 by Liying Ma)Henan Scientific Innovation Talent Team,Department of Education(19IRTSTHN001 by Wen Zhao,China)China Postdoctoral Science Foundation(2020M672249 by Liying Ma)Natural Science Foundation of Henan Province(No.212300410392 by Liying Ma,China)。
文摘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 bearing4-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 positive 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.
