The history of Z-VAD-FMK, a tool for understanding the significance of caspase inhibition.

Dr. Robert Smith is one of the pioneers in histochemistry. One of his most important achievements is the recognition of proteolysis as a major physiological and pathophysiological process. As a consequence, he developed selective fluorogenic and chromogenic substrates and specific inhibitors of proteases that allow the (histochemical) analysis of protease activity. One of the latest successes is the design of Z-VAD-fluoromethylketone (FMK), the specific caspase inhibitor, that is a key compound for studies on apoptosis. Its development was originally meant for therapeutic use but unforeseen cytotoxicity of a metabolic derivative of the FMK compound disabled its potential as a drug. However, as a tool for fundamental research it is a great success. The history of Z-VAD-FMK is an example of the creative brain and the tireless perseverance of Robert Smith for which histochemistry and cytochemistry owes him so much. This history of Z-VAD-FMK is a well-deserved tribute at the occasion of his 70th birthday.