Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design.

Abstract

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the de novo design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, in vivo efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.

• Authors: Justin D Dietrich, Kenton L Longenecker, Noel S Wilson, Christian Goess, Sanjay C Panchal, Steven L Swann, Andrew M Petros, Adrian D Hobson, David Ihle, Danying Song, Paul Richardson, Kenneth M Comess, Philip B Cox, Amanda Dombrowski, Kathy Sarris, Diana L Donnelly-Roberts, David B Duignan, Arthur Gomtsyan, Paul Jung, A Chris Krueger, Suzanne Mathieu, Andrea McClure, Vincent S Stoll, Jill Wetter, John A Mankovich, Philip J Hajduk, Anil Vasudevan, Robert H Stoffel, Chaohong Sun
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 1 Pg. 417-429 (01 14 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 33378180 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biological Products
• Ligands
• Tumor Necrosis Factor-alpha

Topics

• Administration, Oral
• Allosteric Regulation
• Animals
• Arthritis, Rheumatoid (drug therapy)
• Autoimmune Diseases (drug therapy)
• Biological Products (chemical synthesis, pharmacology, therapeutic use)
• Drug Design
• Ligands
• Mice
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)