ADAM21 Inhibitors

Chemical inhibitors of ADAM21 function by interacting with the protein's active site, which is crucial for its proteolytic activity. Marimastat and Batimastat, both broad-spectrum matrix metalloprotease (MMP) inhibitors, can inhibit ADAM21 by binding to this active site. The inhibition process involves the chelation of the zinc ion within the enzyme's active site, which is essential for the proteolytic activity of ADAM21. Similarly, GM6001, a hydroxamate-based inhibitor, can target the metalloprotease domain of ADAM21, effectively blocking its ability to interact with substrates. This is because the metalloprotease domain of ADAM proteins shares structural and functional characteristics with MMPs, making MMP inhibitors suitable candidates for inhibiting ADAM21.

Other chemical inhibitors like TAPI-0, designed primarily to inhibit tumor necrosis factor-alpha converting enzyme (TACE), another member of the ADAM family, can inhibit ADAM21 by emulating the action of natural tissue inhibitors of metalloproteinases (TIMPs). This mimicry prevents the enzyme from performing its natural proteolytic functions. Selective inhibitors like ARP-100, which primarily target MMP-2, along with Ro 32-3555, SB-3CT, and CP-471474, inhibit the enzyme by binding to its catalytic site. Prinomastat, known for its inhibitory action on multiple MMPs, can also inhibit ADAM21 by engaging the active site in a similar manner, thereby hindering the enzyme's interaction with its specific substrates. These inhibitors collectively work by altering the proteolytic function of ADAM21, which is pivotal for its role in cell signaling and the shedding of cell surface proteins.