Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches

  • J Med Chem. 2020 Dec 10;63(23):15050-15071. doi: 10.1021/acs.jmedchem.0c01732.
Hai-Yun Xiao  1 ,  Ning Li  1 ,  James J-W Duan  1 ,  Bin Jiang  1 ,  Zhonghui Lu  1 ,  Khehyong Ngu  1 ,  Joseph Tino  1 ,  Lisa M Kopcho  1 ,  Hao Lu  1 ,  Jing Chen  1 ,  Andrew J Tebben  1 ,  Steven Sheriff  1 ,  ChiehYing Y Chang  1 ,  Joseph Yanchunas Jr  1 ,  Deepa Calambur  1 ,  Mian Gao  1 ,  David J Shuster  1 ,  Vojkan Susulic  1 ,  Jenny H Xie  1 ,  Victor R Guarino  1 ,  Dauh-Rurng Wu  1 ,  Kurt R Gregor  1 ,  Christine B Goldstine  1 ,  John Hynes Jr  1 ,  John E Macor  1 ,  Luisa Salter-Cid  1 ,  James R Burke  1 ,  Patrick J Shaw  1 ,  T G Murali Dhar  1
Affiliations
  • 1. Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
PMID: 33261314 DOI: 10.1021/acs.jmedchem.0c01732
Abstract

Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor Alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF Receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a Collagen antibody-induced Arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.

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