2. Academic Validation
  3. Discovery of the thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors

Discovery of the thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors

  • Bioorg Med Chem. 2026 Apr:135:118571. doi: 10.1016/j.bmc.2026.118571.
Lu Han 1,  Shumin Zang 2,  Wenxin Li 3,  Hangtian Yue 4,  Xiaoqian Zhou 5,  Jie Chen 2,  Meiyu Geng 6,  Wenhu Duan 7,  Zuoquan Xie 8,  Zhengsheng Zhan 9
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, PR China.
  • 2 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.
  • 3 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.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; ShanghaiTech University, Shanghai 201210, PR China.
  • 5 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; ShanghaiTech University, 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; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
  • 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: [email protected].
  • 9 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China. Electronic address: [email protected].
PMID: 41564501 DOI: 10.1016/j.bmc.2026.118571
Abstract

The adaptor molecule STING is embedded in the endoplasmic reticulum (ER) membrane. In innate immunity, STING is a critical cascade in regulating the cytoplasmic DNA-recognizing signaling. Aberrant STING signaling facilitates the host body to secrete an intolerable level of inflammatory cytokines as well as interferons, causing interferonopathies including STING-associated infantile vasculopathy, familial chilblain lupus, and amyotrophic lateral sclerosis. Suppressing the disordered STING signaling has demonstrated to ameliorate the inflammatory impairments of interferonopathy diseases. In this article, we provide the discovery of thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors. Through the structure-activity relationship (SAR) exploration, we identified compound 11 h as an oral-available STING inhibitor possessing cellular mouse- or human-STING inhibiting IC50 of 8.8 or 11.5 nM. Compound 11 h markedly hindered the cellular STING cascade in both murine- and human-derived cells. Furthermore, 11 h achieved robust in vivo activity opposing MAS-2-caused systemic inflammatory damage and cisplatin-caused renal inflammation and injury. Proposed binding model of 11 h-STING indicates that 11 h engages the transmembrane area of STING.

Keywords

Anti-inflammatory; Inhibitor of STING; Interferons; Thieno[2,3-b][1,4]thiazin.

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