Prospects for caspase inhibitors.

Programmed cell death, or apoptosis, is executed by a series of Cysteine Aspartyl Proteases (Caspases) that form a proteolytic cascade. Each caspase functions either to activate downstream caspases by proteolytic cleavage and/or to proteolytically cleave cellular substrates. Increased levels of apoptosis and caspase activity are frequently observed at sites of cellular damage in both acute (e.g. myocardial infarction, stroke, sepsis) and chronic (e.g. Alzheimer's, Parkinson's and Huntington's Disease) indications. Thus, inhibition of caspase activity with the aim of reducing cell death, and hence tissue damage, is predicted to be therapeutically beneficial. Herein we outline different approaches that have been taken to identify small-molecule caspase inhibitors that include both traditional (e.g. HTS, structure-based design and substrate analog approaches) and novel screening technologies (e.g. Tethering). In addition, the characterization of inhibitors emerging from these programs will also be presented. Many of these compounds demonstrate efficacy in a wide range of animal models; however, only two examples of caspase inhibitors have progressed to clinical testing. Here we will discuss issues (both compound and mechanism related) associated with developing a caspase program in the pharmaceutical industry.