MT-MMP-3 Inhibitors

Chemical inhibitors of MT-MMP-3 employ a variety of mechanisms to impede the proteolytic activity of this protein. Marimastat, for example, is a broad-spectrum MMP inhibitor that binds directly to the catalytic domain of MT-MMP-3. This binding prevents MT-MMP-3 from interacting with and degrading extracellular matrix proteins, which is a fundamental role of this protease. Similarly, Ilomastat, or GM6001, is a hydroxamate-based inhibitor that chelates the zinc ion within the MT-MMP-3 active site. By sequestering this crucial metal ion, Ilomastat inhibits the enzyme's ability to cleave peptide bonds. Batimastat also targets MT-MMP-3 by mimicking the substrate's transition state, occupying the active site, and consequently blocking the enzyme from processing its natural substrates. Prinomastat and AG3340, which is another name for prinomastat, both inhibit MT-MMP-3 by interacting with the zinc-binding group within the enzyme's active site, thereby obstructing substrate interaction and cleavage. SB-3CT selectively inhibits the gelatinase function of MT-MMP-3 by binding to its catalytic domain, which directly prevents the proteolysis of substrate proteins. TAPI-0 and TAPI-2 are inhibitors with mechanisms that include blocking the active site of MT-MMP-3, preventing the enzyme from engaging with its substrates and performing its proteolytic function. PD166793, a synthetic compound, and MMI-166, which selectively inhibits MMPs, both function by binding to the zinc active site of MT-MMP-3, crucial for its enzymatic activity. Ro 28-2653 operates by chelating the metal ion in the active site of MT-MMP-3, an action that is essential for the protease's catalytic function. This inhibition halts the enzymatic activity, effectively stopping MT-MMP-3 from breaking down components of the extracellular matrix. Andecaliximab, despite being a monoclonal antibody and not a small molecule, can bind to MT-MMP-3 and inhibit its function by obstructing its active site, demonstrating that inhibitors of MT-MMP-3 can vary widely in structure but converge on a common mechanism of inhibiting the enzyme's active site and thus its function. These inhibitors operate by directly interfering with the catalytic activity of MT-MMP-3, establishing a blockade that prevents substrate cleavage and subsequent protein degradation, which is a critical aspect of MT-MMP-3's role in physiological processes.