Discovery of a New Tetrahydroquinoline-Based Chemotype for STING Inhibition with In Vivo Efficacy against Acute Kidney Injury

  • J Med Chem. 2026 May 14;69(9):11044-11071. doi: 10.1021/acs.jmedchem.6c00162.
So Hyeon Jeong  1  2 ,  Ji Hun Wi  3  4 ,  Jiyoon Park  1  2 ,  Yeseul Kim  3 ,  Jinhee Mun  1 ,  Hayeon Kim  1 ,  Joo-Youn Lee  1  5 ,  Soyoung Yoon  6 ,  Hankum Park  6  7  8 ,  Gyu Yong Song  2 ,  Cheulhee Jung  4 ,  Sanghee Lee  3  9 ,  Hyejin Kim  1  5  10
Affiliations
  • 1. Infectious Diseases Therapeutic Research Center, Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
  • 2. Department of Pharmacy, College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
  • 3. Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
  • 4. Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
  • 5. Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon 34113, Republic of Korea.
  • 6. Department of Dental Sciences, School of Dentistry, Seoul National University, Seoul 08826, Republic of Korea.
  • 7. Institute for Data Innovation in Science, Seoul National University, Seoul 08826, Republic of Korea.
  • 8. Dental Multiomics Center, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
  • 9. KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 10. School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
PMID: 41999331 DOI: 10.1021/acs.jmedchem.6c00162
Abstract

Aberrant activation of the stimulator of interferon genes (STING) drives excessive type I interferon and inflammatory responses implicated in autoimmune and inflammatory diseases, including acute kidney injury (AKI). Here, we report the discovery of a tetrahydroquinoline-based STING inhibitor chemotype, represented by KSI-028, that expands the limited scaffold diversity of current small-molecule STING inhibitors. Mechanistic studies suggest that KSI-028 engages STING through a noncanonical, likely allosteric, binding mode with sustained target engagement. KSI-028 potently suppressed STING-dependent signaling and reduced type I interferon and pro-inflammatory cytokine production in both murine and human cells. In a cisplatin-induced AKI mouse model, KSI-028 attenuated renal and hepatic injury and down-regulated STING-associated inflammatory gene expression. These findings establish the tetrahydroquinoline scaffold as a promising foundation for the development of next-generation STING inhibitors with alternative target engagement modes for the treatment of STING-driven inflammatory disorders.

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