Discovery of selective HDAC/BRD4 dual inhibitors as epigenetic probes

Jingjing Chen; Yalei Li; Jie Zhang; Minmin Zhang; Aihuan Wei; Hongchun Liu; Zhicheng Xie; Wenming Ren; Wenwen Duan; Zhuo Zhang; Aijun Shen; Youhong Hu

doi:10.1016/j.ejmech.2020.112868

Discovery of selective HDAC/BRD4 dual inhibitors as epigenetic probes

Eur J Med Chem. 2021 Jan 1:209:112868. doi: 10.1016/j.ejmech.2020.112868. Epub 2020 Oct 13.

Authors

Jingjing Chen¹, Yalei Li², Jie Zhang¹, Minmin Zhang², Aihuan Wei³, Hongchun Liu², Zhicheng Xie¹, Wenming Ren³, Wenwen Duan³, Zhuo Zhang¹, Aijun Shen⁴, Youhong Hu⁵

Affiliations

¹ State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China.
² Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China.
³ State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
⁴ Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China. Electronic address: shenaj@simm.ac.cn.
⁵ State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, China. Electronic address: yhhu@simm.ac.cn.

PMID: 33077265
DOI: 10.1016/j.ejmech.2020.112868

Abstract

According to the binding mode of ABBV-744 with bromodomains and the cape space of HDAC, the novel selective HDAC/BRD4 dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. Evaluating the biomolecular activities through SARs exploration identified three kinds of selective dual inhibitors 41c (HDAC1/BRD4), 43a (pan-HDAC/BRD4) and 43d (HDAC6/BRD4(BD2)), whose target-related cellular activities in MV-4-11 cells were also confirmed. Significantly, the selective dual inhibitor 41c (HDAC1/BRD4) exhibited synergistic effects against MV-4-11 cells, which strongly induced G0/G1 cell cycle arrest and apoptosis, and the first HDAC6/BRD4(BD2) dual inhibitor was found. This study provides support for selective HDAC/BRD4 dual inhibitors as epigenetic probes based on pyrrolopyridone core for the future biological evaluation in different cancer cell lines.

Keywords: Anticancer; BRD4; HDAC; Selective dual inhibitors.

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Drug Design
Drug Discovery
Drug Screening Assays, Antitumor
Epigenesis, Genetic / drug effects
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / pharmacology*
Humans
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology
Models, Molecular
Neoplasms / drug therapy
Neoplasms / genetics
Neoplasms / metabolism
Pyridines / chemistry
Pyridines / pharmacology
Pyridones / chemistry
Pyridones / pharmacology
Pyrroles / chemistry
Pyrroles / pharmacology
Transcription Factors / antagonists & inhibitors*
Transcription Factors / metabolism

Substances

Antineoplastic Agents
BRD4 protein, human
Cell Cycle Proteins
Histone Deacetylase Inhibitors
Hydroxamic Acids
Pyridines
Pyridones
Pyrroles
Transcription Factors
ABBV-744