Halogen-methyl hybridization unlocks orally bioavailable STING agonist for tumor immunotherapy

  • Eur J Med Chem. 2026 Mar 15:306:118594. doi: 10.1016/j.ejmech.2026.118594.
Guo-Feng Xin  1 ,  Qiang-Sheng Zhu  1 ,  Nan-Nan Chen  1 ,  Lin-Lin Li  1 ,  Ye-Ling Zhou  1 ,  Si-Shuo Liu  1 ,  Si-Jia Gong  2 ,  Bei-Duo Wu  2 ,  Yin-Quan Huang  1 ,  Qi-Dong You  3 ,  Xiao-Li Xu  4
Affiliations
  • 1. State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 3. State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
PMID: 41633117 DOI: 10.1016/j.ejmech.2026.118594
Abstract

The activation of the stimulator of interferon genes (STING) represents a pivotal strategy in tumor immunotherapy. Currently, there is a pressing need for more small-molecule STING agonists to advance into clinical trials. In this study, we developed a series of benzofuran derivatives as novel non-nucleotide STING agonists through structure-based drug design strategies. Systematic optimization yielded the candidate compound X41, which exhibits potent STING agonist activity and favorable drug-like properties. Structural refinement was achieved through R3-position ''chloro'' (Cl) and R1-position ''methyl effect'' (CH3) substituents, optimizing the balance between target potency and membrane permeability. Mechanistic characterization revealed that X41 demonstrates dose-dependent activation of the STING signaling pathway in THP1-Dual cells, significantly inducing downstream IFN-β and CXCL10 expression. In the MC38 syngeneic tumor model, oral administration of X41 (50 mg/kg) achieved substantial tumor growth inhibition (TGI = 88.04 %), while intraperitoneal dosing (20 mg/kg) induced complete tumor regression in 50 % of the treated mice. Pharmacokinetic profiling demonstrated favorable plasma exposure and metabolic stability, with an oral half-life (T1/2) of 9.92 h. These integrated preclinical studies establish X41 as a structurally novel oral STING agonist with significant translational potential, positioning it as a promising candidate for the immunotherapy of solid tumors.

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