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

Autor:	Dietrich JD; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Longenecker KL; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Wilson NS; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Goess C; AbbVie Bioresearch Center, 100 Research Drive, Worcester, Massachusetts 01605, United States., Panchal SC; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Swann SL; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Petros AM; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Hobson AD; AbbVie Bioresearch Center, 100 Research Drive, Worcester, Massachusetts 01605, United States., Ihle D; AbbVie Bioresearch Center, 100 Research Drive, Worcester, Massachusetts 01605, United States., Song D; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Richardson P; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Comess KM; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Cox PB; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Dombrowski A; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Sarris K; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Donnelly-Roberts DL; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Duignan DB; AbbVie Bioresearch Center, 100 Research Drive, Worcester, Massachusetts 01605, United States., Gomtsyan A; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Jung P; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Krueger AC; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Mathieu S; AbbVie Bioresearch Center, 100 Research Drive, Worcester, Massachusetts 01605, United States., McClure A; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Stoll VS; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Wetter J; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Mankovich JA; AbbVie Bioresearch Center, 100 Research Drive, Worcester, Massachusetts 01605, United States., Hajduk PJ; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Vasudevan A; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Stoffel RH; AbbVie Bioresearch Center, 100 Research Drive, Worcester, Massachusetts 01605, United States., Sun C; Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Jan 14; Vol. 64 (1), pp. 417-429. Date of Electronic Publication: 2020 Dec 30.
DOI:	10.1021/acs.jmedchem.0c01280
Abstrakt:	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:	MEDLINE
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