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<p>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(1<i>H</i>)-carboxamide STING inhibitors. SAR study allowed us to identify compound <b>3b</b> as a potent STING inhibitor with human- and mouse-STING inhibitory IC<sub>50</sub> values of 6.2 and 12.5&#xa0;nM, respectively. It also markedly suppressed the activation of the STING pathway in both human and murine cells. Furthermore, compound <b>3b</b> exhibited preferable in vivo protective efficacy against cisplatin-induced acute kidney injury.</p> Graphical abstract <p></p>

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

  • 期刊论文

  • 发表日期：

    2025年12月11日

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  • Xiaoqian Zhou,
  • Shumin Zang,
  • Shanyan Yao,
  • Hongfei Zhou,
  • Xiyuan Wang,
  • Meiyu Geng,
  • Zhengsheng Zhan,
  • Zuoquan Xie,
  • Wenhu Duan

摘要

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.

Graphical abstract