Description of Invention:
This disclosure concerns novel serine protease inhibitors and methods for using the inhibitors to reduce tumor progression and/or metastasis. Embodiments of the inhibitors are highly effective, selective inhibitors of matriptase, which has been implicated in tissue remodeling associated with the growth of cancerous tumors and cancer metastasis.
Angiogenesis and tumor invasion require that the normal tissue surrounding the tumor be broken down in a process referred to as tissue remodeling. Tissue remodeling is accomplished by a host of enzymes that break down the proteins in the normal tissue barriers comprising the extracellular matrix. Among the enzymes associated with degradation of the extracellular matrix and tissue remodeling are a number of proteases. The expression of some of these proteases has been correlated with tumor progression.
The disclosed compounds can be used to inhibit matriptase, MTSP1, or both, in vitro and in vivo and thus can be used in the prevention or treatment of conditions characterized by abnormal or pathological serine protease activity. For example, the compounds are useful for prevention or treatment of conditions characterized by the pathological degradation of the extracellular matrix, such as conditions characterized by neovascularization or angiogenesis, including cancerous conditions, particularly metastatic cancerous conditions where matriptase is implicated. The disclosed compounds can be used to decrease the degradation of the cellular matrix and thereby reduce concomitant tumor progression and metastasis. Conditions characterized by abnormal or pathological serine protease activity that can be treated according to the disclosed method include those characterized by abnormal cell growth and/or differentiation, such as cancers and other neoplastic conditions. Typical examples of cancers that may be treated according to the disclosed inhibitors and method include colon, pancreatic, prostate, head and neck, gastric, renal, and brain cancers.
