Grant: Project Grant

Worldwide, 1 in 3 women and 1 in 5 men over 50 years of age will experience osteoporotic fractures. Current osteoporosis treatments have various shortcomings such as poor bone quality and several skeletal and non-skeletal side effects. Therefore major investments have been made into the development of more effective drugs that are less prone to side effects. Due to efforts of ourselves and many others it has been discovered that bone-degrading cathepsin K (CatK) is a highly suitable drug target whose inhibition led to increased bone quality and reduced fracture rates in clinical osteoporosis trials. Although there is little doubt about the validity of CatK as a drug target, none of the CatK inhibitors have been approved because of various safety concerns. Based on our research, this might be due to the multifunctional character of the enzyme, where total inhibition leads to the observed side effects. However, the osteoporosis relevant activity of this enzyme is limited to its potent collagenase activity, which should be selectively blocked. Based on our previous studies on the mechanism of collagen degradation by CatK, we have developed a strategy to specifically block the collagen-degrading activity without affecting other biologically important actions of this protease. We termed this novel and innovative type of drugs "ectosteric inhibitors" and our proposed project is aimed at characterizing these substrate-specific drugs at their molecular, cellular and in vivo levels of action and efficacy as anti-resorptives. We have identified compounds that have a similar bone-preserving potency in cell assays and in an osteoporosis mouse model similar to the most advanced clinically evaluated CatK inhibitor without affecting non-bone-related pathways. This proposal introduces the novel concept of substrate-selective inhibitors that are superior to all previously developed protease drugs and aims to develop potent, efficacious, and side effect free osteoporosis drugs.