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

Tumor necrosis factor alpha (TNF alpha) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-kappa B and MAPK signaling pathways. The development of biologic drugs that inhibit TNF alpha has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNF alpha 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 TNF alpha 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 TNF alpha antibody.

Automated summary

TNFα is a key soluble cytokine involved in systemic inflammation, and development of drugs targeting it has proven challenging. A fragment-based drug discovery approach led to the identification of lead compounds with improved binding efficiency and drug-like properties.