ADAM20 Inhibitors

Chemical inhibitors of ADAM20 can employ a variety of mechanisms to inhibit the proteolytic function of this metalloprotease. Marimastat and BB-2516, for example, are known to bind directly to the metalloprotease active sites of proteins like ADAM20, thereby preventing substrate access and cleavage. This binding likely involves chelation of the zinc ion integral to ADAM20's proteolytic mechanism, effectively inactivating its enzymatic function. Similarly, GM6001 inhibits proteases by interacting with the zinc-binding domain, a common target for many metalloprotease inhibitors, which leads to the inhibition of the enzymatic activity of ADAM20. Batimastat (aka BB-94) operates through a comparable mode of action, binding to the catalytic site of ADAM20 and preventing the coordination of the zinc ion necessary for the protease to exert its function.

Further along this line, TAPI-0, TAPI-1, and TAPI-2, originally developed as inhibitors of TACE, another ADAM family member, can inhibit ADAM20 by obstructing substrate access to the active site or by interfering with the protease domain's ability to cleave its substrates. The inhibition is achieved due to the structural similarities within the catalytic domains of these proteases, allowing these inhibitors to cross-react. KB-R7785, although primarily an ADAM17 inhibitor, can inhibit ADAM20 by mimicking this inhibitory mechanism, indicating a possible conservation of inhibitor binding sites across the ADAM family. PD166793 and WAY-170523, both MMP inhibitors, can inhibit ADAM20 by a mechanism likely involving interaction with the metalloprotease domain, similar to other MMP inhibitors, and thus preventing proteolytic activity. Ro 32-3555 also falls into this category of MMP inhibitors, which can inhibit ADAM20 by binding to its catalytic site, a method effective in inhibiting protease activity across a spectrum of metalloproteases. Through these mechanisms, these chemicals can inhibit the functional activity of ADAM20, each by engaging with the structural and catalytic features necessary for its protease activity.