Strategies to Target ADAM17 in Disease: From Its Discovery to the iRhom Revolution

Abstract

For decades, disintegrin and metalloproteinase 17 (ADAM17) has been the object of deep investigation. Since its discovery as the tumor necrosis factor convertase, it has been considered a major drug target, especially in the context of inflammatory diseases and cancer. Nevertheless, the development of drugs targeting ADAM17 has been harder than expected. This has generally been due to its multifunctionality, with over 80 different transmembrane proteins other than tumor necrosis factor α (TNF) being released by ADAM17, and its structural similarity to other metalloproteinases. This review provides an overview of the different roles of ADAM17 in disease and the effects of its ablation in a number of in vivo models of pathological conditions. Furthermore, here, we comprehensively encompass the approaches that have been developed to accomplish ADAM17 selective inhibition, from the newest non-zinc-binding ADAM17 synthetic inhibitors to the exploitation of iRhom2 to specifically target ADAM17 in immune cells.

Cerebral Autoregulation in Subarachnoid Hemorrhage

“…The remaining targets (TNF, S1P, S1P 2 R, CFTR, and ROCK) may all be functionally linked into a pathological signaling chain (75). Briefly, our previous work shows that soluble TNF [i.e., TNF released via shedding (281)(282)(283)] enhances S1P signaling in cerebral arteries following SAH, by augmenting S1P synthesis and preventing S1P degradation (87,93). Specifically, TNF enhances S1P synthesis via sphingosine kinase 1 activation (284); simultaneously, it reduces S1P degradation, via the downregulation of CFTR protein expression (87,93), a critical S1P transporter (285,286) that sequesters S1P from its receptors (287).…”

The Synergy of ADAM17-Induced Myocardial Inflammation and Metabolic Lipids Dysregulation During Acute Stress: New Pathophysiologic Insights Into Takotsubo Cardiomyopathy

“…Remarkably, direct injection of TIMP3 in the heart has been shown to downregulate ADAM17's activity by binding to its catalytic domain, thereby inactivating it (74,75). Also, PDIs can directly interact with the MPD of ADAM17, where it catalyzes the isomerization of two disulfide bridges, thus downregulating ADAM17's activity (76,77). A study conducted by Bax et al, revealed that the binding of intergrin α 5 β 1 to ADAM17 via its disintegrin domain, downregulated its activity by affecting its mediated cell adhesion and migration (78).…”

ADAM 17 and Epithelial-to-Mesenchymal Transition: The Evolving Story and Its Link to Fibrosis and Cancer

“…EMT can be induced by different extracellular triggers such as various soluble and juxtacrine factors and physical interactions with the ECM through integrin receptors; in addition, the EMT programme can be activated in response to cellular stressors such as hypoxia or therapeutic targets [ 52 , 53 ]. Since ADAM17 mediates the ectodomain shedding of various pro-inflammatory molecules, it is of no surprise that ADAM17 has attracted attention as a potential driver of inflammation and also repurposed pathologically during fibrosis [ 2 , 42 ]. In support of this notion, ADAM17 is overactivated or overexpressed in numerous human chronic inflammatory diseases, and it is noted that EMT represents a convergence point between inflammation and the progression of degenerative fibrotic diseases and cancer [ 2 , 42 ].…”

“…Since ADAM17 mediates the ectodomain shedding of various pro-inflammatory molecules, it is of no surprise that ADAM17 has attracted attention as a potential driver of inflammation and also repurposed pathologically during fibrosis [ 2 , 42 ]. In support of this notion, ADAM17 is overactivated or overexpressed in numerous human chronic inflammatory diseases, and it is noted that EMT represents a convergence point between inflammation and the progression of degenerative fibrotic diseases and cancer [ 2 , 42 ]. Several well-designed studies have shown correlations between the increased levels of ADAM17 expression and the severity of fibrosis in patients with degenerative fibrotic diseases.…”

“…The proteolytic release of transmembrane proteins, the so-called ectodomain shedding, is a crucial step in a wide variety of cellular and biological processes necessary for many fundamental physiological functions, while dysregulated shedding results in detrimental effects on cell behaviour and is linked to severe diseases [ 1 , 2 ]. The Disintegrin and Metalloproteinase 17 (ADAM17) holds in the plasmatic membrane of several cell types and is able to cleave multiple varieties of cell surface proteins [ 3 ].…”