IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v10y2019i1d10.1038_s41467-019-13616-1.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    The Institute for Protein Innovation, 4 Blackfan Circle)

  • David Fox III

    (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)

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.

Suggested Citation

  • James O’Connell & John Porter & Boris Kroeplien & Tim Norman & Stephen Rapecki & Rachel Davis & David McMillan & Tracy Arakaki & Alex Burgin & David Fox III & Tom Ceska & Fabien Lecomte & Alison Malon, 2019. "Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13616-1
    DOI: 10.1038/s41467-019-13616-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-019-13616-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-019-13616-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13616-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.