2. Academic Validation
  3. Discovery of isoindoline-2(1H)-carboxamide STING inhibitors as anti-inflammatory agents

Discovery of isoindoline-2(1H)-carboxamide STING inhibitors as anti-inflammatory agents

  • Mol Divers. 2025 Dec 11. doi: 10.1007/s11030-025-11424-y.
Xiaoqian Zhou # 1 2 3,  Shumin Zang # 4 5,  Shanyan Yao 1,  Hongfei Zhou 1 5,  Xiyuan Wang 4,  Meiyu Geng 4 5 6,  Zhengsheng Zhan 7 8,  Zuoquan Xie 9 10,  Wenhu Duan 11 12
Affiliations

Affiliations

  • 1 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China.
  • 2 Lingang Laboratory, Shanghai, 200031, People's Republic of China.
  • 3 School of Physical Science & Technology, ShanghaiTech University, Shanghai, 201210, People's Republic of China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China.
  • 5 University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
  • 6 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, People's Republic of China.
  • 7 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China. [email protected].
  • 8 University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China. [email protected].
  • 9 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China. [email protected].
  • 10 University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China. [email protected].
  • 11 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China. [email protected].
  • 12 University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 41379298 DOI: 10.1007/s11030-025-11424-y
Abstract

STING (stimulator of interferon genes) is an endoplasmic reticulum-resident membrane-spanning protein that is widely expressed in mammalian cells and functions as a central regulator for the innate immunity. Aberrant activation of the STING axis due to loss-of-function or gain-of-function mutation leads to various autoimmune and autoinflammatory disorders such as Aicardi-Goutières syndrome, systemic lupus erythematosus, and STING-associated vasculopathy with onset in infancy. Here we report the design, synthesis, and structure-activity relationship (SAR) of the isoindoline-2(1H)-carboxamide STING inhibitors. SAR study allowed us to identify compound 3b as a potent STING inhibitor with human- and mouse-STING inhibitory IC50 values of 6.2 and 12.5 nM, respectively. It also markedly suppressed the activation of the STING pathway in both human and murine cells. Furthermore, compound 3b exhibited preferable in vivo protective efficacy against cisplatin-induced acute kidney injury.

Keywords

Inhibitors; Isoindoline-2(1H)-carboxamide; SAR; Stimulator of interferon genes.

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