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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Dietrich JD,Longenecker KL,Wilson NS,Goess C,Panchal SC,Swann SL,Petros AM,Hobson AD,Ihle D,Song D,Richardson P,Comess KM,Cox PB,Dombrowski A,Sarris K,Donnelly-Roberts DL,Duignan DB,Gomtsyan A,Jung P,Krueger AC,Madoi
10.1021/acs.jmedchem.0c01280subject
Has Abstractpub_date
2021-01-14 00:00:00pages
417-429issue
1eissn
0022-2623issn
1520-4804journal_volume
64pub_type
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