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

Zhimin Zhang; Shaohua Hou; Hongli Chen; Ting Ran; Fei Jiang; Yuanyuan Bian; Dewei Zhang; Yanle Zhi; Lu Wang; Li Zhang; Hongmei Li; Yanmin Zhang; Weifang Tang; Tao Lu; Yadong Chen

doi:10.1016/j.bmcl.2016.04.034

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. Epub 2016 Apr 22.

Authors

Zhimin Zhang¹, Shaohua Hou¹, Hongli Chen¹, Ting Ran², Fei Jiang¹, Yuanyuan Bian¹, Dewei Zhang¹, Yanle Zhi¹, Lu Wang¹, Li Zhang¹, Hongmei Li¹, Yanmin Zhang², Weifang Tang¹, Tao Lu³, Yadong Chen⁴

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle Proteins
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Epigenesis, Genetic / drug effects*
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
Structure-Activity Relationship
Transcription Factors / antagonists & inhibitors*
Transcription Factors / metabolism

Substances

Antineoplastic Agents
BRD4 protein, human
Cell Cycle Proteins
Histone Deacetylase Inhibitors
Isoxazoles
Nuclear Proteins
Transcription Factors
Histone Deacetylases