Cathepsin B inhibitors as potential anti-metastatic agents

Abstract

Classical cancer treatments have focused on the use of cytotoxic agents and/or radiation therapy that target both tumour and normal cells. Consequently, current cancer treatments with chemotherapeutic agents are subject to limitations associated with high toxicity and resistance. There is a need to develop new agents and therapies that will permit long-term administration without compromising the patient. The individual steps of angiogenesis and metastasis during cancer progression are now well understood and present new targets for chemotherapy. The cysteine protease cathepsin B has been linked to the invasive steps during the metastatic process and provides a new target for drug development. Cathepsin B has also been implicated in other disease states with aberrant protein turnover such as muscular dystrophy, inflammatory airway diseases, bone and joint disorders and pancreatitis. Examination of the x-ray crystal structure of cathepsin B reveals the presence of an insertion loop extending for 18 residues that obstructs part of the active-site cleft. This ‘occluding loop’ is a unique feature that can be targeted for the development of specific inhibitors of cathepsin B as potential therapeutic agents. Inhibitors can be classified as to whether they act in a reversible or irreversible manner. This review details members of both of these classes of inhibitors and their therapeutic applications.

• anti-metastatic
• cathepsin B
• cysteine protease
• inhibitor