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 sideeffect of the most common breast and prostate cancer. Aside from human suffering enormousfinancial health care costs are added to the treatment of these diseases. Current treatmentshave various shortcomings and side effects, which include increased cancer risks, atypicalfractures, bone necrosis, infections, and vascular problems. There is clearly a need for moreeffective and safer treatments. Unfortunately, little progress has been made in recent years.Most treatments attack rather non-specifically entire cells or block complex pathways, whichis likely causing the side effects. In contrast, the protease, cathepsin K, is solely responsiblefor the bone degradation and significantly contributes to joint erosion. Its inhibition has beenshown to effectively reduce fracture rates in post-menopausal women. However, thistreatment also had severe side effects leading to the termination of the further development ofcathepsin K inhibitors. Our research has identified and verified a novel type of cathepsin Kinhibitors without causing any of the side effects seen in clinical trials. Interestingly, a majorsource 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 modelwithout any observable side effects. This project will expand this approach and will generatemore potent and druggable derivatives from the herbal compounds. Compounds will beanalyzed in arthritis and bone cancer mouse models. We anticipate that these compounds willhave a superior efficacy with no or fewer side effects than current treatment regimes. Thisproject requires a strong interdisciplinary collaboration between chemists, pharmaceuticalscientists, biochemists, and animal model researchers and will provide an excellentopportunity for the training of students.