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

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.