Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay

Zhifeng Chen; Hao Zhang; Shien Liu; Yiqian Xie; Hao Jiang; Wenchao Lu; Heng Xu; Liyan Yue; Yuanyuan Zhang; Hong Ding; Mingyue Zheng; Kunqian Yu; Kaixian Chen; Hualiang Jiang; Cheng Luo

doi:10.1039/c7md00083a

Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay

Medchemcomm. 2017 Mar 17;8(6):1322-1331. doi: 10.1039/c7md00083a. eCollection 2017 Jun 1.

Authors

Zhifeng Chen^{1

2

3}, Hao Zhang^{1

3}, Shien Liu^{1

3}, Yiqian Xie⁴, Hao Jiang^{1

3}, Wenchao Lu^{1

3}, Heng Xu^{1

3}, Liyan Yue^{1

3}, Yuanyuan Zhang¹, Hong Ding^{1

4}, Mingyue Zheng¹, Kunqian Yu¹, Kaixian Chen¹, Hualiang Jiang^{1

2

3}, Cheng Luo^{1

3}

Affiliations

¹ Drug Discovery and Design Center , State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 555 Zuchongzhi Road , Shanghai 201203 , China . Email: 10110700070@fudan.edu.cn ; Email: hding@simm.ac.cn ; Email: cluo@simm.ac.cn ; Tel: +86 21 50806600.
² School of Life Science and Technology , ShanghaiTech University , 100 Haike Road , Shanghai 201210 , China.
³ University of Chinese Academy of Sciences , 19 Yuquan Road , Beijing 100049 , China.
⁴ School of Pharmacy , Shanghai University of Traditional Chinese Medicine , China.

Abstract

As a member of the bromodomain and extra terminal domain (BET) protein family, BRD4 is closely related to cancers and other diseases. Small-molecule BRD4 inhibitors have already demonstrated promising potential for the therapy of BRD4-related cancers. In this study, we report the discovery and evaluation of a novel category of BRD4 inhibitors, which share a trimethoxy ring and target the first bromodomain of the human BRD4 protein. The IC₅₀ value of the most potent compound, DC-BD-03, is 2.01 μM. In addition, a high-resolution crystal structure of the compound DC-BD-29 with the first bromodomain of BRD4 was determined, which revealed the binding mode and facilitated further structure-based optimization. These compounds exhibited anti-proliferation activity, caused cell cycle arrest, and induced apoptosis in human leukemia MV4-11 cells. Thus, the results presented in this study indicated the potential of this series of compounds as drug candidates for the therapy of BRD4-related cancers.