期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 27, 期 9, 页码 1871-1881出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.03.037
关键词
BRD4; BD1 inhibitor; Cancer; Fibrosis; Computer-aided drug design; Structure-activity relationship
资金
- National Natural Science Foundation of China [81573287, 81773640]
- Hunan Province Strategic Emerging Industry Science and Technology Key Project [2016GK4028]
- Postgraduates innovation subject of Central South University [2018zzts875]
- Key research and development project of Hainan Province, Haikou, China [ZDYF2017092]
- Hainan Province Key Research and Development Project Haikou, China [ZDYF2016128]
Bromodomain-containing protein 4 (BRD4), consisting of two tandem bromodomains (BD1 and BD2), is key epigenetic regulator in fibrosis and cancer, which has been reported that BD1 and BD2 have distinct roles in posttranslational modification. But there are few selective inhibitors toward those two domains. Herein, this study designed and synthesized a series of novel selective BRD4-BD1 inhibitors, using computer-aided drug design (CADD) approach focused on exploring the difference of the binding pockets of BD1 and BD2, and finding the His437 a crucial way to achieve BRD4-BD1 selectivity. Our results revealed that the compound 3u is a potent selective BRD4-BD1 inhibitor with IC50 values of 0.56 p.M for BD1 but > 100 mu M for BD2. The compound exhibited a broad spectrum of anti-proliferative activity against several human cancer and fibroblastic cell lines, which might be related to its capability of reducing the expression of c-Myc and collagen I. Furthermore, it could induce apoptosis in A375 cells. To the contrary, the selective BD2 inhibitor, RVX-208, did not indicate any of these activities. Our findings highlight that the function of BRD4-BD1 might be predominant in fibrosis and cancer. And it is rational to further develop novel selective BRD4-BD1 inhibitors.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据