Nonproteolytic functions of matrix metalloproteinases in pathology and insights for the development of novel therapeutic inhibitors

Abstract

Structural selectivity-in fact, the lack thereof-has been invoked as an explanation for the failure of matrix metalloproteinase (MMP) inhibitors as oncology drugs. However, functional selectivity is needed to develop a good drug. In addition, many drugs (including in oncology) act by interfering with signaling functions. The present market of successful biologicals contains many monoclonal antibodies, such as signaling inhibitors, with antitumor necrosis factor (anti-TNF) being the flagship of an armada. However, aside from its many pathogenic functions, TNF also plays physiological (ie, beneficial) roles. As long as the inhibition of detrimental functions supersedes the negative side effects, anti-TNF will be used. For such reasons, it is critical to know all the functions of MMPs, ideally before inhibitors are used as drugs. Here, we briefly summarize the known catalytic MMP functions and focus on the noncatalytic roles of these proteins, with an emphasis on their signaling effects. Indeed, recent studies have addressed the biology of multimolecular signaling complexes containing MMPs and the tissue inhibitors of metalloproteinases. These complexes are observed in solution (eg, as heteromers or homomultimers) and at the cell surfaces (eg, as docking complexes and signaling receptors). Consequently, a good understanding of the broader contexts-from the molecular, to the cellular and tissue levels-in which such molecular complexes operate will provide essential insights into direct new drug developments. This is exemplified with clinical and recent preclinical successes.