Discovery of an Orally Active Small-Molecule Tumor Necrosis Factor-α Inhibitor

  • J Med Chem. 2020 Aug 13;63(15):8146-8156. doi: 10.1021/acs.jmedchem.0c00377.
Weiguang Sun  1 ,  Yanli Wu  2 ,  Mengzhu Zheng  1 ,  Yueying Yang  2 ,  Yang Liu  2 ,  Canrong Wu  1 ,  Yirong Zhou  1 ,  Yonghui Zhang  1 ,  Lixia Chen  2 ,  Hua Li  1  2
Affiliations
  • 1. Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 2. Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
PMID: 32667202 DOI: 10.1021/acs.jmedchem.0c00377
Abstract

Tumor necrosis factor α (TNF-α) is an important therapeutic target for rheumatoid arthritis, inflammatory bowel disease, and septic hepatitis. In this study, structure-based virtual ligand screening combined with in vitro and in vivo assays were applied. A lead compound, benpyrine, could directly bind to TNF-α and block TNF-α-trigged signaling activation. Furthermore, the endotoxemic murine model showed that benpyrine could attenuate TNF-α-induced inflammation, thereby reducing liver and lung injury. Meanwhile, administration of benpyrine by gavage significantly relieved the symptoms of collagen-induced arthritis and imiquimod-induced psoriasiform inflammation in mice. Thus, our study discovered a novel, highly specific, and orally active small-molecule TNF-α inhibitor that is potentially useful for treating TNF-α-mediated inflammatory and autoimmune disease.

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