Structure-based molecular insights into matrix metalloproteinase inhibitors in cancer treatments

Protease inhibitors are of considerable interest as anticancer agents. Matrix metalloproteinases (MMPs) were the earliest type of proteases considered as anticancer targets. The developments of MMP inhibitors (MMPIs) by pharmaceutical companies can be dated from the early 1980s. Thus far, none of the over 50 MMPIs entering clinical trials have been approved. This work summarizes the reported studies on the structure of MMPs and complexes with ligands and inhibitors, based on which, the authors analyzed the clinical failures of MMPIs in a structural biological manner. Furthermore, MMPs were systematically compared with urokinase, a protease-generating plasmin, which plays similar pathological roles in cancer development; the reasons for the clinical successes of urokinase inhibitors and the clinical failures of MMPIs are discussed.

Ligand-based design of anticancer MMP2 inhibitors: a review

MMP2, a Zn2+-dependent metalloproteinase, is related to cancer and angiogenesis. Inhibition of this enzyme might result in a potential antimetastatic drug to leverage the anticancer drug armory. In silico or computer-aided ligand-based drug design is a method of rational drug design that takes multiple chemometrics (i.e., multi-quantitative structure–activity relationship methods) into account for virtually selecting or developing a series of probable selective MMP2 inhibitors. Though existing matrix metalloproteinase inhibitors have shown plausible pan-matrix metalloproteinases (MMP) activity, they have resulted in various adverse effects leading to their being rescinded in later phases of clinical trials. Therefore a review of the ligand-based designing methods of MMP2 inhibitors would result in an explicit route map toward successfully designing and synthesizing novel and selective MMP2 inhibitors.