Development of iRhom2/ADAM17 inhibitors for the treatment of inflammatory diseases.

Nowadays, there is an urgent need for new therapies for chronic inflammatory diseases such as rheumatoid arthritis (RA). ADAM17 also known as TACE (TNFα converting enzyme) is a metalloproteinase expressed upon the cell surface, which controls the release of soluble TNFα (tumour necrosis factor alpha), the major driver of inflammation. So far, all attempts to find ADAM17 selective inhibitors have failed.1 Consequently, more specific inhibitory strategies were required, leading to the development of anti-TNF antibodies. However, these antibodies determined clinical improvement in less than 50% of treated RA patients,2 therefore an alternative inflammatory treatment is still needed. Soluble TNFα is released by the cleavage of its ectodomain by ADAM17, whose shedding activity is intimately regulated by iRhoms (inactive rhomboids).3 Of the two mammalian iRhoms, only iRhom2 is expressed in macrophages, making the iRhom2/ADAM17 complex a promising target for the treatment of inflammatory diseases. To date, the only literature evidence of iRhom2/ADAM17 inhibitors comes from patent WO 2023/056365,4 from which we selected the three most active compounds (1, 2 and 3) and fine-tuned the synthetic procedures to obtain the desired products with high yields. Meanwhile, we employed the SiteMap algorithm to identify putative binding sites within the iRhom2/ADAM17 complex and assess their druggability. Bioisosteric studies were also performed on the most active compound 2 to enhance its affinity for the complex. Among the molecules showing a good IFD (Induced Fit docking) score, sixteen derivatives with good synthetic feasibility were selected and synthesized: compounds 4-16 (Figure 1).