Small-molecule Drug Discovery for the Tumor Necrosis Factor Pathway

The tumor necrosis factor (TNF) pathway plays an important role in the immune system homeostasis. It is involved in a broad range of inflammatory and autoimmune diseases. Hence, there is a need for small-molecules that can interfere with this pathway. Herein we have focused on two different ways of targetting the TNF pathway.

The first strategy we used is to develop molecules that bind to the TNF receptors, by relying on fragment-based drug discovery (Figure i.). We screened our libraries of around 500 fragments by ¹⁹F NMR. Then the hits were validated by surface plasmon resonance (SPR), and finally the validated compounds were taken for X-ray crystallography. Based on these results we synthesized around 50 analogs of the main scaffold that were all evaluated by SPR for their binding to TNFR1. Here, we disclose a group of molecules that bind to TNFR1 with μM affinity.

The second approach we used is to aim for the degradation of the MAPK p38, a more downstream target that is involved in the TNF pathway. We used the PROTAC technology to try and develop a selective degrader of the p38γ isoform. We synthesized and tested several molecules to check for degradation of the different p38 isoforms. This allowed us to identify a degrader of the α and β isoforms.