Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design PMID: 33378180

Target-related Cytokines

2026-09-23

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

J Med Chem. 2021 Jan 14;64(1):417-429. doi: 10.1021/acs.jmedchem.0c01280.

Justin D Dietrich ¹ , Kenton L Longenecker ¹ , Noel S Wilson ¹ , Christian Goess ² , Sanjay C Panchal ¹ , Steven L Swann ¹ , Andrew M Petros ¹ , Adrian D Hobson ² , David Ihle ² , Danying Song ¹ , Paul Richardson ¹ , Kenneth M Comess ¹ , Philip B Cox ¹ , Amanda Dombrowski ¹ , Kathy Sarris ¹ , Diana L Donnelly-Roberts ¹ , David B Duignan ² , Arthur Gomtsyan ¹ , Paul Jung ¹ , A Chris Krueger ¹ , Suzanne Mathieu ² , Andrea McClure ¹ , Vincent S Stoll ¹ , Jill Wetter ¹ , John A Mankovich ² , Philip J Hajduk ¹ , Anil Vasudevan ¹ , Robert H Stoffel ² , Chaohong Sun ¹

Affiliations

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.