Novel and Selective Inactivators for Matrix Metalloproteases Involved in Breast Cancer Metastasis

摘要

The research was a multidisciplinary and multifaceted endeavor on matrix metalloproteases (MMPs) as target for intervention of cancer. The specific targets were gelatinases, MMP-2 and MMP-9, two members of the MMP family We generated three-dimensional computational models for gelatinases (and other MMPs) that have been made available to the scientific community. The structural knowledge and sequence information were used collectively to address the issue of evolution of MMPs and their diversification of function. Furthermore, we investigated the issues of inhibition (binding) of MMPs by tissue protein inhibitors, the TIMPs, in an extensive investigation with homogeneous preparations of the proteins. This knowledge was used in de novo design of synthetic inhibitors for gelatinases that are highly specific for these enzymes over the other related MMPs. One synthetic inhibitor proved to be highly potent and selective inhibitor for gelatinases. This is the first mechanism-based inhibitor for targeting of MMPs, and it shows a number of features (discussed herein) that sets it apart from the known MMP inhibitors.