ADAM25 Inhibitors

Chemical inhibitors of ADAM25 function by targeting its metalloprotease domain, which is essential for its proteolytic activity. Marimastat, as a broad-spectrum matrix metalloprotease inhibitor, binds to the zinc-binding site within the metalloprotease domain of ADAM25, obstructing its ability to cleave substrate molecules. Similarly, Batimastat and Ilomastat (GM6001) are synthetic inhibitors that also target the active site of metalloproteases. These inhibitors are designed to mimic substrate transition states, thereby effectively inhibiting the catalytic activity of ADAM25. CGS 27023A and PD 166793 function in a comparable manner, occupying the active site of ADAM25 to prevent its substrate interaction and subsequent proteolysis. Ro 32-3555, although initially characterized as a collagenase inhibitor, exerts its inhibitory action on ADAM25 by blocking its metalloprotease domain, which shares functional similarities with that of collagenases.

Additionally, TAPI-0 and KB-R7785, while primarily identified as inhibitors of tumor necrosis factor-α converting enzyme (TACE/ADAM17), inhibit ADAM25 by targeting the sheddase activity, which ADAM25 possesses as well. This hindrance prevents ADAM25 from releasing its substrates from the cell surface. WAY-170523, known for its selectivity towards MMP-13, can inhibit ADAM25 by a similar mechanism of action, which involves the blockade of the metalloprotease domain, leading to an overall decrease in the proteolytic activity of ADAM25. Each chemical, by binding to or interfering with the metalloprotease domain of ADAM25, ensures the protein's inability to interact with and process its specific substrates, thereby functionally inhibiting the protein's activity.