Structure-based design, synthesis and in vitro antiproliferative effects studies of novel dual BRD4/HDAC inhibitors

Mingfeng Shao; Linhong He; Li Zheng; Lingxiao Huang; Yuanyuan Zhou; Taijing Wang; Yong Chen; Mingsheng Shen; Fang Wang; Zhuang Yang; Lijuan Chen

doi:10.1016/j.bmcl.2017.07.054

Structure-based design, synthesis and in vitro antiproliferative effects studies of novel dual BRD4/HDAC inhibitors

Bioorg Med Chem Lett. 2017 Sep 1;27(17):4051-4055. doi: 10.1016/j.bmcl.2017.07.054. Epub 2017 Jul 21.

Authors

Affiliations

¹ Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, PR China.
² Sichuan Provincial Key Laboratory for Organ Transplantation Translation Medicine, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, PR China.
³ Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, PR China. Electronic address: chenlijuan125@163.com.

PMID: 28765013
DOI: 10.1016/j.bmcl.2017.07.054

Abstract

Histone acetylation marks play important roles in controlling gene expressions and are removed by histone deacetylases (HDACs). These marks are read by bromodomain and extra-terminal (BET) proteins, whose targeted inhibitors are under clinical investigation. BET and HDAC inhibitors have been demonstrated to be synergistically killing in Mycinduced murine lymphoma. Herein, we combine the inhibitory activities of BET and HDAC into one molecule through structure-based design method and evaluate its function. The majority of these synthesized compounds showed inhibitory activity against second bromdomains(BRD) of BRD4 and HDAC1. Among them, 16ae presented anti-proliferative effects against human acute myelogenous leukemia (AML) cell lines in vitro, and 16ae is confirmed to reduce the expression of Myc by Western blot analysis. Those results indicated that 16ae is a potent dual BRD4/HDAC inhibitor and deserves further investigation.

Keywords: AML; BET; Dual inhibitors; HDAC; Myc.

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
Histone Deacetylase 1 / antagonists & inhibitors*
Histone Deacetylase 1 / metabolism
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Humans
Models, Molecular
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
Nuclear Proteins
Transcription Factors
HDAC1 protein, human
Histone Deacetylase 1