2. Academic Validation
  3. Discovery of triazoloquinoxaline as novel STING agonists via structure-based virtual screening

Discovery of triazoloquinoxaline as novel STING agonists via structure-based virtual screening

  • Bioorg Chem. 2020 Jul;100:103958. doi: 10.1016/j.bioorg.2020.103958.
Hui Hou 1,  Ruirui Yang 2,  Xiaohong Liu 2,  Xiaolong Wu 3,  Sulin Zhang 4,  Kaixian Chen 5,  Mingyue Zheng 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Shanghai Institute for Advanced Immunochemical Studies, and School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China.
  • 3 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
  • 4 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
  • 5 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
  • 6 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
PMID: 32470762 DOI: 10.1016/j.bioorg.2020.103958
Abstract

Stimulator of interferon genes (STING) is an endoplasmic reticulum adaptor facilitating innate immune signaling. Activation of STING leads to expression of interferons (IFNs) and pro-inflammatory cytokines which is associated with Antiviral and antitumor responses. It is imperative to discovery potent compounds that precisely modulate STING. Herein, we describe the discovery of triazoloquinoxaline 1a as a novel STING agonist via Structure-based Virtual Screening. Specifically, biochemical and cell-based assays suggested that 1a stimulated concentration-dependently mRNA expression of IFNβ, CXCL-10 and IL-6. Furthermore, 1a significantly induced phosphorylation of STING, TANK-binding kinases1 (TBK1) and interferon regulatory factor 3 (IRF3), suggesting the activation of STING and its downstream TBK1-IRF3 signaling axis. In addition, 1a activated secretion of secreted Alkaline Phosphatase (SEAP) in dose-dependent manner and EC50 was 16.77 ± 3.814 μM, which is comparable with EC50 of 2'3'-cGAMP (9.212 ± 2.229 μM). These studies revealed that 1a is a promising STING agonist possessing the potential to be further developed for Antiviral and antitumor treatment.

Keywords

Agonist; Drug design; STING; Triazoloquinoxaline; Virtual screening.

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