2. Academic Validation
  3. DWL-4-140: A allene small molecule targeting STING that alleviates lupus-like phenotype in Trex1-/- mice

DWL-4-140: A allene small molecule targeting STING that alleviates lupus-like phenotype in Trex1-/- mice

  • Biomed Pharmacother. 2023 Jul 20;165:115188. doi: 10.1016/j.biopha.2023.115188.
Hekang Du 1,  Meng Kou 2,  Weili Deng 3,  Xueyuan Zhou 1,  Xiaoxiong Zhang 1,  Zhengrong Huang 4,  Bowen Ren 1,  Xingting Cai 1,  Shan Xu 1,  Yu Chen 5,  Lizhu Chen 5,  Chuanben Chen 6,  Hongli Bao 7,  Qi Chen 8,  Daliang Li 9
Affiliations

Affiliations

  • 1 Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, PR China.
  • 2 Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, PR China; Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, PR China.
  • 3 Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, PR China; Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, PR China.
  • 4 Department of Integrative Medicine, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province 350117, PR China.
  • 5 Cancer Bio-immunotherapy Center, Clinical Oncology School of Fujian Medical University & Fujian Cancer Hospital, Fuzhou, Fujian Province, PR China; Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian Province, PR China.
  • 6 Cancer Bio-immunotherapy Center, Clinical Oncology School of Fujian Medical University & Fujian Cancer Hospital, Fuzhou, Fujian Province, PR China; Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian Province, PR China. Electronic address: ccb@fjmu.edu.cn.
  • 7 Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, PR China. Electronic address: hlbao@fjirsm.ac.cn.
  • 8 Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, PR China. Electronic address: chenqi@fjnu.edu.cn.
  • 9 Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, PR China. Electronic address: daliangli@fjnu.edu.cn.
PMID: 37480829 DOI: 10.1016/j.biopha.2023.115188
Abstract

The innate immune system plays a critical role in the host response against pathogenic microbial Infection. However, aberrant activation of the innate immune pathways is a characteristic feature of various diseases. Thus, targeted drugs must be developed based on the understanding of the innate immune signaling pathways. This study demonstrated that an allene small molecule (DWL-4-140) can efficiently and selectively exert regulatory effects on the stimulator of interferon genes (STING), resulting in the downregulation of DNA-induced interferon responses. Mechanistically, DWL-4-140 targeted the cyclized nucleotide-binding domain (CBD) of STING, inhibiting the assembly of the STING multimeric complex and the recruitment of downstream signaling mediators. In addition to downregulating the 10-carboxymethyl-9-acridanone-induced production of inflammatory factors, DWL-4-140 alleviated the pathological features of Trex1 deletion-induced lupus in mice. Thus, this study demonstrated that DWL-4-140 pharmacologically inhibits STING with potential therapeutic applications in auto-inflammatory diseases.

Keywords

1,4-Sulfimido-cyanation allene; Autoimmunity; Interferon; STING; TREX1.

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