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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.
Highlights
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
This screen identified UCB-6786 (Fig. 1a) and an analogue UCB-6876, which bound to TNF displaying a concentration-dependent response curve and selectivity over the TNF receptor 1 (TNFR1) extracellular domain and control proteins (Fig. 1b)
The slow kinetic profile is unusual for molecules of this size and the resulting curve (Fig. 1c) did not have the square wave shape that is typical of fragment binding
Summary
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. 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 This approach may prove to be a more general mechanism for inhibiting protein–protein interactions. The compound SPD-304 targets TNF directly and has been shown to inhibit activity by destabilising the TNF trimer, resulting in a dimer that is no longer able to interact with receptor[4] This strategy has so far not led to molecules capable of being developed, work is continuing in this area[5,6,7]. This finding has the potential to broaden the availability of the therapeutic benefits of TNF inhibition
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