2. Academic Validation
  3. Targeting epigenetic reader and eraser: Rational design, synthesis and in vitro evaluation of dimethylisoxazoles derivatives as BRD4/HDAC dual inhibitors

Targeting epigenetic reader and eraser: Rational design, synthesis and in vitro evaluation of dimethylisoxazoles derivatives as BRD4/HDAC dual inhibitors

  • Bioorg Med Chem Lett. 2016 Jun 15;26(12):2931-2935. doi: 10.1016/j.bmcl.2016.04.034.
Zhimin Zhang 1,  Shaohua Hou 1,  Hongli Chen 1,  Ting Ran 2,  Fei Jiang 1,  Yuanyuan Bian 1,  Dewei Zhang 1,  Yanle Zhi 1,  Lu Wang 1,  Li Zhang 1,  Hongmei Li 1,  Yanmin Zhang 2,  Weifang Tang 1,  Tao Lu 3,  Yadong Chen 4
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
  • 2 Laboratory of Molecular Design and Drug Discovery, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
  • 3 Laboratory of Molecular Design and Drug Discovery, School of Science, 639 Longmian Avenue, Nanjing 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: lutao@cpu.edu.cn.
  • 4 Laboratory of Molecular Design and Drug Discovery, School of Science, 639 Longmian Avenue, Nanjing 211198, China. Electronic address: ydchen@cpu.edu.cn.
PMID: 27142751 DOI: 10.1016/j.bmcl.2016.04.034
Abstract

The bromodomain protein module and histone deacetylase (HDAC), which recognize and remove acetylated lysine, respectively, have emerged as important epigenetic therapeutic targets in Cancer treatments. Herein we presented a novel design approach for Cancer drug development by combination of bromodomain and HDAC inhibitory activity in one molecule. The designed compounds were synthesized which showed inhibitory activity against bromodomain 4 and HDAC1. The representative dual bromodomain/HDAC inhibitors, compound 11 and 12, showed potent antiproliferative activities against human leukaemia cell line K562 and MV4-11 in cellular assays. This work may lay the foundation for developing dual bromodomain/HDAC inhibitors as potential Anticancer therapeutics.

Keywords

Antiproliferative activity; Bromodomain; Epigenetic; HDAC; Protein–protein interactions.

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