Discovery of Dimeric Arylsulfonamides as Potent ADAM8 Inhibitors

Abstract

The metalloproteinase ADAM8 is upregulated in several cancers but has a dispensable function under physiological conditions. In tumor cells, ADAM8 is involved in invasion, migration, and angiogenesis. The use of bivalent inhibitors could impair migration and invasion through the double binding to a homodimeric form of ADAM8 located on the cell surface of tumor cells. Herein we report the rational design and synthesis of the first dimeric ADAM8 inhibitors selective over ADAM10 and matrix metalloproteinases. Bivalent derivatives have been obtained by dimerizing the structure of a previously described ADAM17 inhibitor, JG26. In particular, derivative 2 was shown to inhibit ADAM8 proteolytic activity in vitro and in cell-based assays at nanomolar concentration. Moreover, it was more effective than the parent monomeric compound in blocking invasiveness in the breast cancer MDA-MB-231 cell line, thus supporting our hypothesis about the importance of inhibiting the active homodimer of ADAM8.

Tumor-derived exosomal ADAM17 promotes pre-metastatic niche formation by enhancing vascular permeability in colorectal cancer

“…Next, we conducted comparative experiments using a selective inhibitor of ADAM17, JG26 [ 22 ], an oral inhibitor of ADAM17, aderbasib [ 23 ], and a selective inhibitor of ADAM10, GI254023X [ 24 ] (Fig. 3 k).…”

“…Subsequently, we conducted in vivo experiments using two ADAM17 inhibitors to suppress the hematogenous metastasis of CRC. One of these ADAM17 inhibitors, JG26, can effectively inhibit the enzymatic activity of ADAM17 at concentrations below 10 nmol while having no significant effects on other ADAM enzymes [ 22 ]. Therefore, JG26 represents a promising ADAM17 inhibitor with good selectivity and a low minimum effective concentration for clinical application as an anti-metastatic drug.…”

Bacterial Zinc Metalloenzyme Inhibitors: Recent Advances and Future Perspectives

“…These elements are common to all the already reported inhibitors of metalloproteinases either of bacterial (such as M4) or human origin, including MMPs [55][56][57] and ADAMs [58,59]. Nowadays, the real challenge is to obtain selective M4 metalloproteinase inhibitors sparing the human endogenous metalloproteinase as the key factor to avoid several side effects.…”

“…The adsorption and metabolism in Caenorhabditis elegans were investigated and compounds 56, 57 and 58 with their respective acetamido prodrugs (59, 60 and 61) were examined. Interestingly, prodrug 61 was the only derivative of this series to be accumulated in the C. elegans, metabolized into its activated form (58) and then oxidized into the corresponding disulfide analogue. Therefore, prodrug 61 could be considered a good starting point for future studies [89].…”