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

• Published in: Bioorganic & medicinal chemistry letters 2016-06, Vol.26 (12), p.2931-2935
• Main Authors: Zhang, Zhimin, Hou, Shaohua, Chen, Hongli, Ran, Ting, Jiang, Fei, Bian, Yuanyuan, Zhang, Dewei, Zhi, Yanle, Wang, Lu, Zhang, Li, Li, Hongmei, Zhang, Yanmin, Tang, Weifang, Lu, Tao, Chen, Yadong
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Bromodomain; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Epigenesis, Genetic - drug effects; Epigenetic; HDAC; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Humans; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - pharmacology; Molecular Structure; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - metabolism; Protein–protein interactions; Structure-Activity Relationship; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.04.034

[Display omitted] 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.