2. Academic Validation
  3. Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

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

  • Nat Commun. 2019 Dec 19;10(1):5795. doi: 10.1038/s41467-019-13616-1.
James O'Connell 1,  John Porter 2,  Boris Kroeplien 2,  Tim Norman 2,  Stephen Rapecki 2,  Rachel Davis 2,  David McMillan 2,  Tracy Arakaki 3,  Alex Burgin 4 5,  David Fox Iii 6,  Tom Ceska 2,  Fabien Lecomte 2,  Alison Maloney 2,  Alex Vugler 2,  Bruce Carrington 2,  Benjamin P Cossins 2,  Tim Bourne 2,  Alastair Lawson 2
Affiliations

Affiliations

  • 1 UCB Pharma, Slough, SL1 3WE, UK. james.oconnell@ucb.com.
  • 2 UCB Pharma, Slough, SL1 3WE, UK.
  • 3 Covance Inc, Princeton, NJ, 08540, USA.
  • 4 Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
  • 5 The Institute for Protein Innovation, 4 Blackfan Circle, Boston, MA, 02115, USA.
  • 6 UCB Pharma, Bainbridge Island, WA, 98110, USA.
PMID: 31857588 DOI: 10.1038/s41467-019-13616-1
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.

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