Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

• Published in: Nature communications 2019-12, Vol.10 (1), p.5795-12, Article 5795
• Main Authors: O’Connell, James, Porter, John, Kroeplien, Boris, Norman, Tim, Rapecki, Stephen, Davis, Rachel, McMillan, David, Arakaki, Tracy, Burgin, Alex, Fox III, David, Ceska, Tom, Lecomte, Fabien, Maloney, Alison, Vugler, Alex, Carrington, Bruce, Cossins, Benjamin P, Bourne, Tim, Lawson, Alastair
• Format: Article
• Language: English
• Subjects: 631/154/309/2144; 631/154/309/2420; 631/154/309/507; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Arthritis; Arthritis, Experimental - drug therapy; Arthritis, Experimental - immunology; Asymmetry; Autoimmune diseases; Cell Line; Crohn's disease; Crystallography, X-Ray; Cytokines; Drug development; Drug Discovery; Drugs; Humanities and Social Sciences; Male; Mice; Molecular Dynamics Simulation; multidisciplinary; Neutrophil Infiltration - drug effects; Neutrophils - drug effects; Neutrophils - immunology; Protein interaction; Protein Multimerization - drug effects; Protein Stability - drug effects; Protein Structure, Quaternary - drug effects; Proteins; Receptors, Tumor Necrosis Factor, Type I - immunology; Receptors, Tumor Necrosis Factor, Type I - metabolism; Recombinant Proteins - isolation & purification; Recombinant Proteins - metabolism; Recombinant Proteins - ultrastructure; Rheumatoid arthritis; Science; Science (multidisciplinary); Signal Transduction - drug effects; Signal Transduction - immunology; Signaling; Structure-Activity Relationship; Treatment Outcome; Trimers; Tumor necrosis factor; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - isolation & purification; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - ultrastructure; Tumor necrosis factor-TNF; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13616-1

Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions. While biologics have been successfully applied in TNF antagonist treatments, there are no clinically approved small molecules that target TNF. Here, the authors discover potent small molecule inhibitors of TNF, elucidate their molecular mechanism, and demonstrate TNF inhibition in vitro and in vivo.