2. Academic Validation
  3. Discovery of a potent and orally bioavailable 3,3-dimethyl-2-oxoindoline STING inhibitor

Discovery of a potent and orally bioavailable 3,3-dimethyl-2-oxoindoline STING inhibitor

  • Eur J Med Chem. 2026 Jan 5:301:118232. doi: 10.1016/j.ejmech.2025.118232.
Wenxin Li 1,  Xiyuan Wang 2,  Shumin Zang 3,  Rongyao Zhou 4,  Hongfei Zhou 1,  Hangtian Yue 5,  Meiyu Geng 6,  Zhengsheng Zhan 7,  Zuoquan Xie 8,  Wenhu Duan 9
Affiliations

Affiliations

  • 1 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
  • 4 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; ShanghaiTech University, School of Life Science & Technology, Shanghai, 201210, PR China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, PR China.
  • 7 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China. Electronic address: zszhan@simm.ac.cn.
  • 8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China. Electronic address: zqxie@simm.ac.cn.
  • 9 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China. Electronic address: whduan@simm.ac.cn.
PMID: 41076779 DOI: 10.1016/j.ejmech.2025.118232
Abstract

Stimulator of interferon genes (STING) plays an imperative role in the innate immune response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Overstimulated STING axis has proven to incur multiple autoimmune or inflammatory diseases, such as Aicardi-Goutières syndrome, systematic lupus erythematosus, and amyotrophic lateral sclerosis. Here we report the discovery of a series of 3,3-dimethyl-2-oxoindoline STING inhibitors. We converted the STING agonist G10 to a STING inhibitor 8a by grafting an indole-3-yl group, and extensive structure-activity relationship (SAR) exploration of 8a allowed us to identify compound 10a as a potent and orally bioavailable STING inhibitor. Biological characterization unraveled that 10a significantly suppressed the STING signaling pathway in human monocytes and murine macrophages, potently alleviated cisplatin-induced kidney injury both in vitro and in vivo, as well as achieved robust anti-inflammatory efficacy on STING agonist-induced inflammation mice model through systemic administration. The proposed binding mode of 10a and the STING protein displays that 10a targets the transmembrane domain of STING.

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