Design, synthesis and biological evaluation of imidazolopyridone derivatives as novel BRD4 inhibitors

Yifei Yang; Pan Chen; Leilei Zhao; Bing Zhang; Changliang Xu; Huibin Zhang; Jinpei Zhou

doi:10.1016/j.bmc.2020.115857

Design, synthesis and biological evaluation of imidazolopyridone derivatives as novel BRD4 inhibitors

Bioorg Med Chem. 2021 Jan 1:29:115857. doi: 10.1016/j.bmc.2020.115857. Epub 2020 Nov 7.

Authors

Yifei Yang¹, Pan Chen¹, Leilei Zhao², Bing Zhang², Changliang Xu³, Huibin Zhang⁴, Jinpei Zhou⁵

Affiliations

¹ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
² Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.
³ Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, PR China. Electronic address: cl.xu81@gmail.com.
⁴ Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: zhanghb80@cpu.edu.cn.
⁵ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: jpzhou668@163.com.

PMID: 33191086
DOI: 10.1016/j.bmc.2020.115857

Abstract

Bromodomain containing protein 4 (BRD4) has been demonstrated to play critical roles in cellular proliferation and cell cycle progression. In this study, using the BRD4 inhibitor Fragment 9 as a lead compound, a series of imidazolopyridone derivatives were designed and tested for their inhibitory activity against BRD4 protein in vitro. Among them, HB100-A7 showed excellent BRD4(1) inhibitory activities with an IC₅₀ value of 0.035 μM in amplified luminescent proximity homogeneous assay (Alphascreen). The result of MTT assay showed that HB100-A7 could suppress the proliferation of pancreatic cancer cells. In addition, flow cytometry further illustrated that HB100-A7 treatment resulted in G0/G1 phase arrest and promoted apoptosis of BxPc3 cells. Furthermore, the in vivo study found that HB100-A7 displayed significant tumor growth inhibition in a pancreatic mouse tumor model (Panc-02). Moreover, IHC staining suggested that HB100-A7 induce cell apoptosis in pancreatic cancer tumor tissue. Together, this study revealed, for the first time, HB100-A7 is a promising lead compound for further development as a new generation of small molecule inhibitors targeting the BRD4 protein.

Keywords: Antitumor; BRD4 inhibitors; Molecular docking; Pancreatic cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle Checkpoints / drug effects
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Male
Mice
Mice, Inbred BALB C
Molecular Docking Simulation
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Pyridones / chemical synthesis
Pyridones / chemistry
Pyridones / pharmacology*
Structure-Activity Relationship
Transcription Factors / antagonists & inhibitors*
Transcription Factors / metabolism

Substances

Antineoplastic Agents
BRD4 protein, human
Cell Cycle Proteins
Imidazoles
Pyridones
Transcription Factors