Grant: Collaborative Health Research Projects (NSERC partnered)

Arthritic diseases affect 15 % of the population and bone cancer is a frequent metastatic side effect of the most common breast and prostate cancer. Aside from human suffering enormous financial health care costs are added to the treatment of these diseases. Current treatments have various shortcomings and side effects, which include increased cancer risks, atypical fractures, bone necrosis, infections, and vascular problems. There is clearly a need for more effective and safer treatments. Unfortunately, little progress has been made in recent years. Most treatments attack rather non-specifically entire cells or block complex pathways, which is likely causing the side effects. In contrast, the protease, cathepsin K, is solely responsible for the bone degradation and significantly contributes to joint erosion. Its inhibition has been shown to effectively reduce fracture rates in post-menopausal women. However, this treatment also had severe side effects leading to the termination of the further development of cathepsin K inhibitors. Our research has identified and verified a novel type of cathepsin K inhibitors without causing any of the side effects seen in clinical trials. Interestingly, a major source of these compounds are certain Chinese herbs traditionally used in skeletal diseases. Recently, we have shown the efficacy of one of these compounds in an osteoporosis model without any observable side effects. This project will expand this approach and will generate more potent and druggable derivatives from the herbal compounds. Compounds will be analyzed in arthritis and bone cancer mouse models. We anticipate that these compounds will have a superior efficacy with no or fewer side effects than current treatment regimes. This project requires a strong interdisciplinary collaboration between chemists, pharmaceutical scientists, biochemists, and animal model researchers and will provide an excellent opportunity for the training of students.