TNF is a major mediator of immunity, inflammation and physiological homeostasis. This implicates a tight regulation to avoid overreaction of the host or expression in an inappropriate location leading to major pathogenic consequences: the initiation and perpetuation of chronic inflammation and the development of cancer and various autoimmune diseases. TNF exerts its properties acting on two different transmembrane receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Whereas TNFR1 is mainly involved in inflammation and tissue degeneration, TNFR2 promotes local homeostatic events like tissue regeneration and immune modulation Currently, five anti-TNF drugs, which prevent the activation of TNF signaling cascade, have been approved on the market against inflammatory diseases such as rheumatoid arthritis. Unfortunately, because of inhibition of TNFR2 related signaling, anti-TNF drugs generate in many patients the onset of serious adverse effects, including infections, autoimmune diseases and malignancies. To avoid this, research began to be interested in the selective targeting of TNFR1. In particular, in prof. Scapozza group in the faculty of pharmacy at the University of Geneva, efforts are made to find small molecules capable of destabilizing the tertiary structure of the DD of TNFR1, as well as to be able to exploit these compounds as putative TOI binders for possible TNFR1 DD PROTACs. To assess the permeability of a future TNFR1 DD PROTAC through the fluorochromasia assay, a Nedd 4 ligand-tetraethylene glycol-fluorescein diacetate PROTAC was synthesized. The presence of an ester bond in this preliminary construct, however, suggested the possibility of a false positive in the fluorochromasia test. In this project the synthesis of a preliminary TNFR1 DD PROTAC with another type of bond (ether or amide) will be explored. Furthermore, through covalent docking we will provide hints on putative functionalization of the current most promising DD destabilizer for its future use as TOI binder.