Chirality-dependent toxicity decoupling: Discovery of a resibufogenin-based L-configured STING inhibitor with superior therapeutic profile for ulcerative colitis

  • Eur J Med Chem. 2026 Jul 11:318:119146. doi: 10.1016/j.ejmech.2026.119146.
Jia-Hua Zhuang  1 ,  Qiu-Heng Zhang  1 ,  Si-Yu Zhou  1 ,  Yuting Wen  1 ,  Yiming Li  2 ,  Shoujiao Peng  1 ,  Shaopeng Yu  1 ,  Zixiao Liu  2 ,  Guo-Qiang Lin  3 ,  Chao Zhang  4 ,  Wenbo Ye  5 ,  Jiange Zhang  6 ,  Gu-Zhou Chen  7
Affiliations
  • 1. The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 2. Key Laboratory of Structure-based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 3. The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, 200032, China. Electronic address: [email protected].
  • 4. Department of Emergency Medicine, The Peking University Third Hospital, No. 49, North Garden Rd., Haidian District, Beijing, 100191, China. Electronic address: [email protected].
  • 5. The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: [email protected].
  • 6. The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: [email protected].
  • 7. The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: [email protected].
PMID: 42470935 DOI: 10.1016/j.ejmech.2026.119146
Abstract

STING, a central component of the cGAS-STING innate immune signaling pathway, is implicated in various autoimmune and inflammatory disorders when aberrantly activated. In this study, an L-configured homoproline derivative Z55 was obtained through structural optimization of the natural product resibufogenin (RBG), which exhibited approximately threefold greater cellular inhibitory activity against STING than RBG (IC50 = 0.40 ± 0.04 μM for Z55 vs. 1.42 ± 0.11 μM for RBG), and maintained favorable in vitro safety. Surface plasmon resonance (SPR) analysis confirmed high-affinity binding of Z55 to hSTING (KD = 2.31 μM), and a cellular thermal shift assay (CETSA) further demonstrated that Z55 directly engages endogenous STING in living cells, with a thermal stabilization of 4.31 ± 0.7 °C. Mechanistic studies, including DTT stability and SPR reversibility assays, support a non covalent interaction mode, while molecular docking provided structural insight into the binding interface. Mechanistically, Z55 inhibited STING phosphorylation and downstream activation of p-TBK1 and p-IRF3, leading to decreased levels of key inflammatory cytokines (IL-1β, IL-6, and TNF-α) in both colon tissue and serum of mice with ulcerative colitis. Importantly, this series of compounds exhibited a marked chiral-toxicity separation, with the L-configuration identified as the optimal pharmacophore for both efficacy and safety. Collectively, these findings highlight Z55 as a promising STING-targeting lead candidate for the treatment of inflammatory diseases.

Keywords
Chiral-toxicity separation; Inflammatory diseases; L-configured homoproline; Resibufogenin; STING inhibitor; cGAS-STING signaling.
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