Metastatic spread of cancer via proteolytic degradation of host biomatrix continues to be the greatest barrier to cancer cure. Two key matrix-degrading metalloproteinases (MMPs), MMP-2 and -9, are implicated in these tumor progression events in humans. They are, therefore, targets for potential anticancer drug design because of their unique substrate specificity and tumor-related activities. The overall goal of this project is to design, synthesize and develop novel nonpeptidyl inhibitors selective for human MMP-2 and -9 as potential antimetastatic agents. A concerted approach based on novel chemical templates, enzyme-inhibitor analysis and a new human bioscreening model will be employed. The synthesis of new conformationally-restrained MMP inhibitors will involve specific substitutions at the P1-P1 subsites of sulfonamide molecules. Based on pilot studies, we postulate that our active site-directed molecular modifications will render high potency and selectivity to inhibitors in target MMPs. Our team effort will have two specific goals: 1. Develop novel MMP-selective nonpeptidyl inhibitors using conformational-restriction chemistry and structure-assisted modeling strategies, and 2. Evaluate functional efficacy of lead MMP inhibitors using our defined human bioassays of tumor angiogenesis, invasion and metastasis, and initiate pharmacological studies. Phase I tasks will identify new inhibitor templates necessary for the synthesis of second-generation potent MMP-specific compounds. Parallel structure-function studies of MMP-2 and -9 with model inhibitors will provide new insights to improve pharmacokinetics and bioefficacy. Human tumor bioassays will elucidate the consequences of selective MMP inhibition on early (angiogenesis) and later (invasion) stages of metastasis. 3-D structural studies of MMP catalytic domains will also be exploited to further assist our drug design strategy. This bioevaluation will be clinically relevant for subsequent in vivo testing of potential anticancer agents. Thus, the scientific basis for future clinical trials and rationale for commercialization of new therapeutic drugs should be established for patients with cancers susceptible to MMP-2 and -9 inhibition. PROPOSED COMMERCIAL APLICATION: Successful development of potent MMP-selective inhibitors as anticancer agents will impact both basic & clinical research and be translated into the therapeutic arena. A bioactive antiangiogenic/antimetastic agent would have a potentially large world-wide market. Synthetic inhibitors of key MMPs will also benefit other related biomedical fields including arthritis, fibrosis and vascular biology.
