Discovery of Potent STING Inhibitors Bearing a Difluorobenzodioxol Structural Motif as Potent Anti-Inflammatory Agents

  • J Med Chem. 2025 Apr 24;68(8):8907-8932. doi: 10.1021/acs.jmedchem.5c00580.
Ancheng Shen  1  2  3 ,  Xiyuan Wang  4  5 ,  Qingxuan Chen  1  2 ,  Yan Zhang  4 ,  Fang Wang  6 ,  Yuqiang Li  7 ,  Zhiguo Liu  3 ,  Liufu Deng  1  2 ,  Wanli Ouyang  7 ,  Meiyu Geng  4  5  8 ,  Zilan Song  1  2 ,  Zuoquan Xie  4  5 ,  Ao Zhang  1  2  3  7  9
Affiliations
  • 1. Shanghai Frontiers Science Center for Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2. State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China.
  • 3. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 6. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 7. Shanghai Artificial Intelligence Laboratory, Shanghai 200433, China.
  • 8. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
  • 9. The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China.
PMID: 40188441 DOI: 10.1021/acs.jmedchem.5c00580
Abstract

Given the critical role of STING in autoimmune and inflammatory disorders, the development of targeted small-molecule inhibitors has been a promising strategy for the treatment of these diseases. Nevertheless, the currently reported STING inhibitors suffer from limited structural diversity, species sensitivity, and poor activity; therefore, none are suitable for clinical investigation. Herein, we performed a structural modification campaign on the tool compound 6 (H-151) based on its potential metabolic hotspots. Compound 66, bearing a difluorobenzodioxol moiety, was identified as one of the most potent STING inhibitors with IC50 values of 116 and 96.3 nM for h- and m-STING, respectively. This compound exhibited a notable enhancement in metabolic properties, especially in terms of metabolic stability. A mechanism study verified that 66 engaged with STING in a covalent manner akin to that of 6. In both the cisplatin-induced acute kidney injury and TREX1 D18N mouse models, 66 significantly alleviated tissue injury and inflammation.

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