Claudiu T Supuran, Antoine Dufour
The 23 members of the matrix metalloproteinase (MMP) family are involved in a multitude of physiological processes, such as cell migration, invasion, cell signaling, immune response, fibrosis, extracellular matrix remodeling, tissue homeostasis, but also in a broad range of diseases, among which cancer, inflammation (sepsis, arthritis, asthma, chronic obstructive pulmonary disorder), periodontitis, etc. Their biochemical characterization, expression patterns, role as targets, offtargets or antitargets in many physiologic or pathologic conditions made relevant progress over the last decades. MMP inhibitors (MMPIs) belonging to a variety of classes (hydrozamates, carboxylates, thiols, phosphonates, etc.) are well known. The first/second generations such derivatives, all zinc binders, have been investigated in clinical trials as anticancer agents in the late '90s, with poor results, probably due to their metabolic instability, toxicity and lack of selectivity for the target isoform(s). Recent developments in the field saw the design of highly selective inhibitors for several MMPs, belonging to the modified tetracyclines class, as well as mechanism based, suicide inhibitors belonging to the substituted thiiranes class, exosite and allosteric inhibitors which spare the zinc ion from the enzyme active site. Two compounds are in clinical use for the management of periodontitis (doxycycline, at submicrobial dosages) and abametapir for the treatment of lice infestation. Clinical trials in various types of cancer, in different inflammatory conditions, and microbial infections (tuberculosis) with some of the new generation MMPIs are ongoing, and the expected results will demonstrate their efficacy, probably in combination therapy with other drugs. More selective new inhibitors, better planned clinical trials and a better understanding of the biology/pharmacology of these enzymes may lead to other breakthroughs in the field.