Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design
| Autor: | Kathy Sarris, Philip J. Hajduk, Ihle David C, Diana L. Donnelly-Roberts, Arthur Gomtsyan, Christian Goess, David B. Duignan, Danying Song, Chaohong Sun, Andrea Mcclure, Adrian D. Hobson, Robert H. Stoffel, Anil Vasudevan, John A. Mankovich, Sanjay C. Panchal, A. Chris Krueger, Steven L. Swann, Kenneth M. Comess, Andrew M. Petros, Wilson Noel S, Jill M. Wetter, Paul G. Richardson, Kenton L. Longenecker, Paul M. Jung, Vincent S. Stoll, Amanda W. Dombrowski, Suzanne Mathieu, Justin D. Dietrich, Philip B. Cox |
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| Rok vydání: | 2020 |
| Předmět: |
Drug
media_common.quotation_subject medicine.medical_treatment Allosteric regulation Administration Oral Arthritis Pharmacology Ligands 01 natural sciences Autoimmune Diseases Arthritis Rheumatoid Mice 03 medical and health sciences Allosteric Regulation In vivo Drug Discovery medicine Animals 030304 developmental biology media_common Biological Products 0303 health sciences Tumor Necrosis Factor-alpha Chemistry Drug discovery medicine.disease Small molecule 0104 chemical sciences 010404 medicinal & biomolecular chemistry Cytokine Drug Design Molecular Medicine Tumor necrosis factor alpha |
| Zdroj: | Journal of Medicinal Chemistry. 64:417-429 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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