The Future of Cysteine Cathepsins in Disease Management

The newly discovered roles of secreted cysteine cathepsins are dominating preclinical research, with major developments in pain regulation and cancer chemotherapy resistance. Cathepsin K inhibitors, including odanacatib, have all failed in osteoporosis clinical trials, but novel strategies to target cathepsin K are emerging. The antibody–drug conjugate field is dominated by cathepsin-cleavable linkers. First cathepsin-targeting imaging probes have entered clinical trials with favorable initial results. A new concept for targeted drug delivery based on cathepsin-targeting is emerging. Since the discovery of the key role of cathepsin K in bone resorption, cysteine cathepsins have been investigated by pharmaceutical companies as drug targets. The first clinical results from targeting cathepsins by activity-based probes and substrates are paving the way for the next generation of molecular diagnostic imaging, whereas the majority of antibody–drug conjugates currently in clinical trials depend on activation by cathepsins. Finally, cathepsins have emerged as suitable vehicles for targeted drug delivery. It is therefore timely to review the future of cathepsins in drug discovery. We focus here on inflammation-associated diseases because dysregulation of the immune system accompanied by elevated cathepsin activity is a common feature of these conditions. Since the discovery of the key role of cathepsin K in bone resorption, cysteine cathepsins have been investigated by pharmaceutical companies as drug targets. The first clinical results from targeting cathepsins by activity-based probes and substrates are paving the way for the next generation of molecular diagnostic imaging, whereas the majority of antibody–drug conjugates currently in clinical trials depend on activation by cathepsins. Finally, cathepsins have emerged as suitable vehicles for targeted drug delivery. It is therefore timely to review the future of cathepsins in drug discovery. We focus here on inflammation-associated diseases because dysregulation of the immune system accompanied by elevated cathepsin activity is a common feature of these conditions.