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

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.
Feng Wang 1,  Kai-Rui Feng 1,  Jia-Ying Zhao 1,  Jian-Wei Zhang 1,  Xin-Wei Shi 1,  Jian Zhou 2,  Dingding Gao 3,  Guo-Qiang Lin 4,  Ping Tian 5
Affiliations

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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.

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