Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches PMID: 33261314

ADC Targets in Oncology

2026-04-10

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

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.