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.

More than two decades have been spent to develop many families of synthetic matrix metalloproteinases inhibitors (MMPI) as therapeutical agents for serious pathologies. Unfortunately, clinical trials conducted on broad-spectrum inhibitors have yielded disappointing results, especially in the cancer pathology area. Despite these outcomes, some small synthetic MMPI are in advanced trials or launched in clinical ones for cancer, arthritis, periodontal diseases. Today many groups are developing intensive efforts to find new classes of inhibitors characterized by improved potency and, above all, high selectivity against the specific MMP involved in each targeted pathology. The new challenges include the development of new MMPI bearing more effective ZBGs and the development of new allosteric non-zinc binding inhibitors, devoid of ZBGs. An analysis of more recent results in this field reported on journals and patents will be developed, to consider some of the more interesting new highly selective synthetic MMPI, their SARs, the new theoretical approaches used for modelling and the results of their biological evaluations.

Receptor protein tyrosine phosphatase T (PTPRT/PTPρ) is frequently mutated in human cancers including colon, lung, gastric, and skin cancers. More than half of the identified tumor-derived mutations are located in the extracellular part of PTPρ. However, the functional significance of those extracellular domain mutations remains to be defined. Here we report that the extracellular domain of PTPρ mediates homophilic cell-cell aggregation. This homophilic interaction is very specific because PTPρ does not interact with its closest homologue, PTPμ, in a cell aggregation assay. We further showed that all five tumor-derived mutations located in the NH₂-terminal MAM and immunoglobulin domains impair, to varying extents, their ability to form cell aggregates, indicating that those mutations are loss-of-function mutations. Our results suggest that PTPρ may play an important role in cell-cell adhesion and that mutational inactivation of this phosphatase could promote tumor migration and metastasis. (Mol Cancer Res 2008;6(7):1106–13)

Angiotensin II (AngII) has been strongly implicated in hypertension and its complications. Evidence suggests the mechanisms by which AngII elevates blood pressure and enhances cardiovascular remodeling and damage may be distinct. However, the signal transduction cascade by which AngII specifically initiates cardiovascular remodeling, such as hypertrophy and fibrosis, remains insufficiently understood. In vascular smooth muscle cells, a metalloproteinase ADAM17 mediates epidermal growth factor receptor transactivation, which may be responsible for cardiovascular remodeling but not hypertension induced by AngII. Thus, the objective of this study was to test the hypothesis that activation of vascular ADAM17 is indispensable for vascular remodeling but not for hypertension induced by AngII. Vascular ADAM17–deficient mice and control mice were infused with AngII for 2 weeks. Control mice infused with AngII showed cardiac hypertrophy, vascular medial hypertrophy, and perivascular fibrosis. These phenotypes were prevented in vascular ADAM17–deficient mice independent of blood pressure alteration. AngII infusion enhanced ADAM17 expression, epidermal growth factor receptor activation, and endoplasmic reticulum stress in the vasculature, which were diminished in ADAM17-deficient mice. Treatment with a human cross-reactive ADAM17 inhibitory antibody also prevented cardiovascular remodeling and endoplasmic reticulum stress but not hypertension in C57Bl/6 mice infused with AngII. In vitro data further supported these findings. In conclusion, vascular ADAM17 mediates AngII-induced cardiovascular remodeling via epidermal growth factor receptor activation independent of blood pressure regulation. ADAM17 seems to be a unique therapeutic target for the prevention of hypertensive complications.