Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design.
Justin D DietrichKenton L LongeneckerNoel S WilsonChristian GoessSanjay C PanchalSteven L SwannAndrew M PetrosAdrian D HobsonDavid IhleDanying SongPaul RichardsonKenneth M ComessPhilip B CoxAmanda DombrowskiKathy SarrisDiana L Donnelly-RobertsDavid B DuignanArthur GomtsyanPaul M JungA Chris KruegerSuzanne MathieuAndrea McClureVincent S StollJill WetterJohn A MankovichPhilip J HajdukAnil VasudevanRobert H StoffelChaohong SunPublished in: Journal of medicinal chemistry (2020)
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.
Keyphrases
- rheumatoid arthritis
- signaling pathway
- small molecule
- high resolution
- drug discovery
- drug induced
- oxidative stress
- pi k akt
- adverse drug
- mass spectrometry
- cell proliferation
- blood pressure
- binding protein
- type diabetes
- immune response
- toll like receptor
- adipose tissue
- metabolic syndrome
- high throughput
- insulin resistance
- diabetic rats
- reactive oxygen species
- induced apoptosis
- stress induced
- structural basis