Side effect-free cathepsin K targeting drugs for skeletal diseases

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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.