Identification of novel STAT3 inhibitors bearing 2-acetyl-7-phenylamino benzofuran scaffold for antitumour study

Feng Wang; Kai-Rui Feng; Jia-Ying Zhao; Jian-Wei Zhang; Xin-Wei Shi; Jian Zhou; Dingding Gao; Guo-Qiang Lin; Ping Tian

doi:10.1016/j.bmc.2020.115822

Identification of novel STAT3 inhibitors bearing 2-acetyl-7-phenylamino benzofuran scaffold for antitumour study

Bioorg Med Chem. 2020 Dec 15;28(24):115822. doi: 10.1016/j.bmc.2020.115822. Epub 2020 Oct 22.

Authors

Feng Wang¹, Kai-Rui Feng¹, Jia-Ying Zhao¹, Jian-Wei Zhang¹, Xin-Wei Shi¹, Jian Zhou², Dingding Gao³, Guo-Qiang Lin⁴, Ping Tian⁵

Affiliations

¹ The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
² Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663N Zhongshan Road, Shanghai 200062, China. Electronic address: jzhou@chem.ecnu.edu.cn.
³ The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663N Zhongshan Road, Shanghai 200062, China. Electronic address: gaodingding@shutcm.edu.cn.
⁴ The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
⁵ The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China. Electronic address: tianping@shutcm.edu.cn.

PMID: 33126089
DOI: 10.1016/j.bmc.2020.115822

Abstract

Signal transducer and activator of transcription 3 (STAT3) is identified as a promising target for multiple cancer therapy and attracts widespread concern. Herein, we reported the discovery of a series of 2-acetyl-7-phenylamino benzofuran derivatives as STAT3 inhibitors using scaffold fusion strategy. Further structure activity relationship study led to the discovery of compound C6, which displayed the most potent anti-proliferation activities against MDA-MB-468 cells (IC₅₀ = 0.16 μM). Western blot assay demonstrated that C6 inhibited the activation of STAT3 (Tyr705) without influencing the phosphorylation of STAT1 (Tyr701). Further mechanistic studies indicated that C6 caused a notable G2/M cycle-arresting and early apoptosis in a concentration-dependent manner in MDA-MB-468 cells. Finally, molecular modelling study elucidated the binding mode of C6 in STAT3 SH2 domain.

Keywords: 2-Acetyl-7-phenylamino benzofurans; Antitumor study; Molecular docking; STAT3 inhibitors; Structure-activity relationships.

Publication types

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

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Benzofurans / chemistry*
Benzofurans / metabolism
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Crystallography, X-Ray
Drug Design
G2 Phase Cell Cycle Checkpoints / drug effects
Humans
Molecular Docking Simulation
Phosphorylation / drug effects
STAT3 Transcription Factor / antagonists & inhibitors*
STAT3 Transcription Factor / metabolism
Structure-Activity Relationship
src Homology Domains

Substances

Antineoplastic Agents
Benzofurans
STAT3 Transcription Factor
STAT3 protein, human
benzofuran