2. Academic Validation
  3. Discovery of indole derivatives as STING degraders

Discovery of indole derivatives as STING degraders

  • Eur J Med Chem. 2025 Sep 15:294:117747. doi: 10.1016/j.ejmech.2025.117747.
Yuxiang An 1,  Yan Zhang 2,  Xin Luo 3,  Yaohan Lan 1,  Meiyu Geng 4,  Wenhu Duan 1,  Zuoquan Xie 5,  Hefeng Zhang 6
Affiliations

Affiliations

  • 1 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Road, Nanjing, Jiangsu, 210023, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Road, Nanjing, Jiangsu, 210023, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: zqxie@simm.ac.cn.
  • 6 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China. Electronic address: zhanghefeng1@simm.ac.cn.
PMID: 40398154 DOI: 10.1016/j.ejmech.2025.117747
Abstract

Aberrant activation of the stimulator of interferon genes (STING) pathway is associated with the development of various inflammatory and autoimmune diseases. Targeting STING for degradation represents a novel strategy for the treatment of these diseases. In this study, we designed and synthesized a series of STING-PROTACs based on a nitro-free covalent warhead and different E3 ligase Binders. The representative compound 2h specifically degraded STING protein through the Proteasome pathway with a DC50 value of 3.23 μM and exhibited sustained degradation activity over 72 h. Further biological studies demonstrated that compound 2h inhibited STING signaling and effectively suppressed immune-inflammatory cytokines both in vitro and in vivo. Moreover, compound 2h offered better safety compared to its warhead molecule and SP23. Collectively, compound 2h is a potent nitro-free covalent STING degrader and warrants further investigation.

Keywords

Autoimmune diseases; Degrader; Inflammatory; PROTAC; STING.

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