2. Academic Validation
  3. Binding pocket-based design, synthesis and biological evaluation of novel selective BRD4-BD1 inhibitors

Binding pocket-based design, synthesis and biological evaluation of novel selective BRD4-BD1 inhibitors

  • Bioorg Med Chem. 2019 May 1;27(9):1871-1881. doi: 10.1016/j.bmc.2019.03.037.
Junlong Ma 1,  Heng Chen 2,  Jie Yang 2,  Zutao Yu 2,  Pan Huang 2,  Haofeng Yang 2,  Bifeng Zheng 2,  Rangru Liu 3,  Qianbin Li 2,  Gaoyun Hu 2,  Zhuo Chen 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, PR China; Department of Good Clinical Practice, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China.
  • 2 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, PR China.
  • 3 Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education & Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, China.
  • 4 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, PR China. Electronic address: cz_job@csu.edu.cn.
PMID: 30926312 DOI: 10.1016/j.bmc.2019.03.037
Abstract

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 post-translational 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 μM for BD1 but >100 μM 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.

Keywords

BD1 inhibitor; BRD4; Cancer; Computer-aided drug design; Fibrosis; Structure-activity relationship.

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