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 rheumatoi...

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Veröffentlicht in:Journal of medicinal chemistry 2021-01, Vol.64 (1), p.417-429
Hauptverfasser: Dietrich, Justin D, Longenecker, Kenton L, Wilson, Noel S, Goess, Christian, Panchal, Sanjay C, Swann, Steven L, Petros, Andrew M, Hobson, Adrian D, Ihle, David, Song, Danying, Richardson, Paul, Comess, Kenneth M, Cox, Philip B, Dombrowski, Amanda, Sarris, Kathy, Donnelly-Roberts, Diana L, Duignan, David B, Gomtsyan, Arthur, Jung, Paul, Krueger, A Chris, Mathieu, Suzanne, McClure, Andrea, Stoll, Vincent S, Wetter, Jill, Mankovich, John A, Hajduk, Philip J, Vasudevan, Anil, Stoffel, Robert H, Sun, Chaohong
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Sprache:eng
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Zusammenfassung: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 design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c01280