Design and syntheses of a bimolecular STING agonist based on the covalent STING antagonist

  • Eur J Med Chem. 2023 Feb 4;250:115184. doi: 10.1016/j.ejmech.2023.115184.
Ruochen Zang  1 ,  Liang Xue  2 ,  Meifang Zhang  3 ,  Xiaoyue Peng  3 ,  Xionghao Li  3 ,  Kaixin Du  3 ,  Chuanqin Shi  4 ,  Yuqian Liu  3 ,  Yuxi Lin  5 ,  Wenwei Han  6 ,  Rilei Yu  3 ,  Qian Wang  7 ,  Jinbo Yang  8 ,  Xin Wang  9 ,  Tao Jiang  10
Affiliations
  • 1. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Department of Clinical Laboratory, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266100, China.
  • 2. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts and Innovation Center for Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266003, China.
  • 3. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • 4. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Center of Translational Medicine, ZiBo Central Hospital, Zibo, 255036, China.
  • 5. Institute of Cancer Biology and Drug Screening, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China.
  • 6. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, 266071, China.
  • 7. Department of Clinical Laboratory, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266100, China; Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, China.
  • 8. Marine Drug Screening and Evaluation Platform, Qingdao National Laboratory for Marine Science and Technology, Ocean University of China, Qingdao, 266071, China.
  • 9. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Marine Drug Screening and Evaluation Platform, Qingdao National Laboratory for Marine Science and Technology, Ocean University of China, Qingdao, 266071, China. Electronic address: [email protected].
  • 10. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts and Innovation Center for Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266003, China. Electronic address: [email protected].
PMID: 36758305 DOI: 10.1016/j.ejmech.2023.115184
Abstract

Cyclic GMP-AMP Synthase and stimulator of interferon genes (cGAS-STING) signaling stimulators, an essential innate immunity component, monitor invading pathogen DNA and damaged self-DNA, making them an appealing target for drug development. The natural STING agonist, 2'3'-cGAMP, mounts and stabilizes the STING homodimer to trigger an Antiviral or antitumor immune responses. However, cyclic-dinucleotide-based STING agonists show limited clinical effects owing to their short half-lives. To explore whether STING-dimer stabilizers could trigger STING signaling instead of cyclic dinucleotide-based molecules, we analyzed the structural characteristics of STING to design and synthesize a series of compounds based on the covalent STING inhibitor C-170, three of which were 23, 26, and 27, exhibited STING-dependent immune activation, both in vitro and in vivo. Compound 23 could act synergistically with cGAMP and other STING agonists as a promising moderate STING agonist. This indicates that promoting STING dimerization is a promising strategy for designing next-generation STING agonists.

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