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Discovery of novel 4-phenylquinazoline-based BRD4 inhibitors for cardiac fibrosis
Acta Pharmaceutica Sinica B ( IF 14.5 ) Pub Date : 2021-07-24 , DOI: 10.1016/j.apsb.2021.07.018
Zhangxu He 1 , Haomiao Jiao 1 , Qi An 1 , Xin Zhang 1 , Dan Zengyangzong 1 , Jiale Xu 1 , Hongmin Liu 1 , Liying Ma 1, 2 , Wen Zhao 1
Affiliation  

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 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.



中文翻译:

发现新的基于 4-苯基喹唑啉的 BRD4 抑制剂用于心脏纤维化

含溴结构域蛋白 4 (BRD4) 作为表观遗传阅读器,可特异性结合组蛋白的乙酰赖氨酸残基,已成为各种疾病的有吸引力的治疗靶点,包括癌症、心脏重塑和心力衰竭。在此,我们描述了使用 2,003,400 个化合物库(烯胺)通过高通量虚拟筛选发现带有 4-苯基喹唑啉骨架的命中 5。然后,进行了构效关系 (SAR) 研究,并使用我们实验室设置的 HTRF 测定法进一步设计、合成和评估了 47 种针对 BRD4 的新 4-苯基喹唑啉衍生物。最终,我们鉴定出化合物 C-34,与阳性对照 JQ1 相比,它具有更好的药代动力学和理化性质以及对 NRCF 和 NRCM 细胞的较低细胞毒性。使用基于计算机的分子对接和细胞热位移分析,我们进一步验证了 C-34 可以在分子和细胞水平上靶向 BRD4。此外,用 C-34 治疗有效地减轻了成纤维细胞的活化体外和体内心脏纤维化,这与 BRD4 下游靶标 c-MYC 的表达降低以及 TGF- β1 /Smad2/3 信号通路的抑制有关。总之,我们的研究结果表明,新型 BRD4 抑制剂 C-34 束缚 4-苯基喹唑啉支架可以作为进一步开发治疗纤维化心血管疾病的先导化合物。

更新日期:2021-07-24
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