2. Academic Validation
  3. Identification of an Orally Bioavailable Quinoline-Based Small-Molecule Tumor Necrosis Factor α (TNF-α) Inhibitor Featuring a Spirocyclic Scaffold

Identification of an Orally Bioavailable Quinoline-Based Small-Molecule Tumor Necrosis Factor α (TNF-α) Inhibitor Featuring a Spirocyclic Scaffold

  • J Med Chem. 2026 Apr 23;69(8):8987-9008. doi: 10.1021/acs.jmedchem.5c03457.
Zeren Sun 1 2,  Wenbin Zhang 2,  Wanyong He 2,  Jie Xu 2,  Boning Wang 2,  Joshua M He 3,  Yuchen Zhang 2,  Pu Chen 2,  Yao Luo 2,  Jia Gu 2,  Hongfeng Gu 2,  Ping Wei 4,  Yanan Sun 2,  Chunxiang Yin 2,  Hanxi Xing 2,  Yannan Luo 2,  Jing-Jing Zhang 2,  Qihua Zhu 2,  Yi Zou 2,  Yungen Xu 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Rice University, Houston, Texas 77005, United States.
  • 4 Hefei Institute of Pharmaceutical Industry Co. Ltd., Hefei 230601, China.
PMID: 41915886 DOI: 10.1021/acs.jmedchem.5c03457
Abstract

Rheumatoid arthritis (RA) is an autoimmune disease that severely restricts patients' daily activities. TNF-α has become one of the important therapeutic targets for RA and Other autoimmune diseases. Herein, we report a series of small-molecule TNF-α inhibitors containing quinoline scaffold and spiro-ring structure. Among them, XS-18 was validated to have strong binding affinity for TNF-α (FP IC50 = 123 nM; KD = 45.9 nM). In addition, XS-18 exhibits significant inhibitory activity against TNF-α mediated inflammatory pathways in vitro. In collagen-induced arthritis (CIA) mouse model, oral administration of XS-18 demonstrated strong anti-inflammatory effects, and its efficacy in promoting joint cartilage repair was superior to that of tofacitinib. XS-18 also exhibiting better pharmacokinetic properties (T1/2 = 7.1 h, F = 56.8%). These findings indicate that XS-18, a small-molecule TNF-α inhibitor, has the potential to serve as an effective oral therapeutic agent for the treatment of autoimmune diseases.

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