MMP inhibitors and cancer treatment trials, limitations and hopes for the future.

Matrix metalloproteinases (MMPs) are a family of enzymes that have been recognized as promising therapeutic and diagnostic targets for the treatment and detection of human cancers. This rises from their unique ability to degrade all components of the extracellular matrix and their overexpression at different stages of tumor progression. The specific involvement of MMPs in the oncogenic processes has speeded up the efforts that have been made for the past 20 years to develop and evaluate MMP inhibitors (MMPIs) as potential anti-cancer agents. However, bringing an MMPI to the point of clinical approval is still a challenge. In this review, we provide an overview of the structure and function of MMPs along with their implication in cancer development. Furthermore, we focus on the literature concerning the development of broad spectrum natural and synthetic MMPIs, with emphasis on their limitations and the disappointing results of most clinical trials. The failure of broad spectrum MMPIs highlighted the need for the development of selective inhibitors that fully discriminate between different members of the MMP family. As a future perspective on the development of potent MMPIs, we also report in this review a novel structure-based strategy developed in our group to design new mini-protein ligands for MMP inhibition by functional motif grafting.