ABSTRACT
Caspases, a family of cysteine proteases, play crucial roles in both maturation of inflammatory cytokines and apoptosis. After the caspase family was discovered, caspase activation was revealed to contribute to large numbers of pathological conditions, while caspase inhibition has been demonstrated to have enormous therapeutic potential in inflammatory diseases and apoptosis-driven disorders. One extremely active area of drug discovery and development targeting apoptosis is the identification of small molecule caspase inhibitors. A number of caspase inhibitors have demonstrated efficacy in a large variety of animal models, and several therapeutics have already progressed into clinical trials such as a caspase-1-specific inhibitor for the treatment of inflammatory diseases, and a pancaspase inhibitor for the treatment of liver diseases (liver preservation injury in liver transplantation and chronic liver disease, i.e., chronic hepatitis C). This chapter will review the present status and future potential of caspase inhibitors and explore the highlights of several caspase inhibitors currently in clinical trials. Focus will be attributed to apoptosis in liver diseases and discovery programs of pancaspase inhibitors against liver diseases. Lastly, this article will discuss the challenges associated with caspase inhibitors, especially mechanism-related toxicity associated with apoptotic caspase inhibition.
