Potential roles of protease inhibitors in anticancer therapy

In physiological conditions, proteases are essential in carrying out biological processes such as gene expression, differentiation, and cell death. However, for their ability to degrade extracellular matrix and proteins, they are strongly associated with cancer progression. A lot of proteases have been linked with increasing tumor metastasis in different human cancers, suggesting their central functions in the metastatic process. The understanding of the proteolytic network in the tumor microenvironment is rapidly increasing because of a raised interest both in protease and in new techniques that allow for comprehensive analysis of protease activity in physiologically relevant conditions. Generally, well-established proteolytic networks consist of multiple steps of activation, several key nodes through which most signals pass, and inhibitors that can regulate activity of different points in such networks. Having a central role in several signaling pathways, proteases represent potential drug targets for a large set of diseases, especially for cancer. Protease inhibitors are compounds able to block proteases function playing a key role in cancer therapies. However, their design is a complex issue since different types of cancers use different proteases at the fluctuating stages of cancer development and no single inhibitor can be used on all classes of proteases. In this chapter, we focused our attention on protease inhibitors, describing their structure and their mechanism of action. There are several pharmaceutical strategies aimed to interfere with the proteases using different inhibitors; they may be split on basis of their mechanism of action and molecular class. In fact, protease inhibitors may be proteins, peptides, or small molecules; they are synthetic peptide-like or small molecules and, based on their inhibition process, may be divided into three main classes: reversible inhibitors, irreversible inhibitors, and engineering inhibitors.