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Issue 6, 2017
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Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay

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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.

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

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Publication details

The article was received on 20 Feb 2017, accepted on 16 Mar 2017 and first published on 17 Mar 2017


Article type: Research Article
DOI: 10.1039/C7MD00083A
Citation: Med. Chem. Commun., 2017,8, 1322-1331
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    Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay

    Z. Chen, H. Zhang, S. Liu, Y. Xie, H. Jiang, W. Lu, H. Xu, L. Yue, Y. Zhang, H. Ding, M. Zheng, K. Yu, K. Chen, H. Jiang and C. Luo, Med. Chem. Commun., 2017, 8, 1322
    DOI: 10.1039/C7MD00083A

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