ETD

• ADAM17
• inflammatory bowel diseases
• iRhoms
• rheumatoid arthritis
• TNF-α

The immune system plays a fundamental role in maintaining homeostasis and protecting the body from injuries and infections. While acute inflammation is essential for defense against pathogens, its dysregulation can lead to chronic inflammatory conditions such as rheumatoid arthritis and inflammatory bowel diseases. These diseases are characterized by the uncontrolled production of soluble TNF-α by activated macrophages. Soluble TNF-α is released by the cleavage of its ectodomain by ADAM17, also known as TACE (TNF-α converting enzyme). Numerous therapeutic strategies have been developed to treat chronic inflammatory diseases, including inhibitory approaches targeting ADAM17 and TNF-α. However, these strategies have not been clinically successful and currently there is an urgent need for novel therapeutic approaches. A revolution in this field was the discovery that ADAM17 activity is intimately regulated by iRhoms (inactive rhomboids), membrane proteins which regulate the conversion of ADAM17 from an inactive to a proteolytically active enzyme, highlighting the iRhom2/ADAM17 complex as a promising target for the treatment of inflammatory diseases. Therefore, the main objective of my master thesis has been the synthesis of a new series of potential iRhom2/ADAM17 inhibitors characterized by an aminophenyl-piperazine core.