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

James O’Connell (), John Porter, Boris Kroeplien, Tim Norman, Stephen Rapecki, Rachel Davis, David McMillan, Tracy Arakaki, Alex Burgin, David Fox, Tom Ceska, Fabien Lecomte, Alison Maloney, Alex Vugler, Bruce Carrington, Benjamin P Cossins, Tim Bourne and Alastair Lawson
Additional contact information
James O’Connell: UCB Pharma
John Porter: UCB Pharma
Boris Kroeplien: UCB Pharma
Tim Norman: UCB Pharma
Stephen Rapecki: UCB Pharma
Rachel Davis: UCB Pharma
David McMillan: UCB Pharma
Tracy Arakaki: Covance Inc
Alex Burgin: Broad Institute of Harvard and MIT
David Fox: UCB Pharma
Tom Ceska: UCB Pharma
Fabien Lecomte: UCB Pharma
Alison Maloney: UCB Pharma
Alex Vugler: UCB Pharma
Bruce Carrington: UCB Pharma
Benjamin P Cossins: UCB Pharma
Tim Bourne: UCB Pharma
Alastair Lawson: UCB Pharma

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13616-1

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