Discovery of Ligands for the TNFR1 Extracellular Domain Using Fragment‐Based Drug Discovery

Tumor necrosis factor receptor 1 (TNFR1) plays a major role in immunoregulation. It is involved in inflammatory and autoimmune diseases like rheumatoid arthritis, psoriasis, Alzheimer’s disease, and multiple sclerosis. However, few small‐molecule inhibitors of TNFR1 have been reported, even though they constitute a good alternative to already existing antibody therapies targeting the TNF pathway. Here, we report the discovery of a new class of molecules for the extracellular domain of TNFR1 using a fragment‐based approach through primary screening by NMR spectroscopy, followed by orthogonal validation by surface plasmon resonance (SPR) and X‐ray crystallography. Guided by these results, we have synthesized 46 analogs with micromolar potency showing up to ∼10‐fold improved affinity toward TNFR1 compared to the fragment hits. These results can provide a structural basis for the discovery of novel TNFR1 inhibitors in the future.