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

Acta Histochem. 2001 Jul;103(3):241-51. doi: 10.1078/0065-1281-00601.


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.

Publication types

  • Editorial
  • Historical Article

MeSH terms

  • Amino Acid Chloromethyl Ketones / history*
  • Amino Acid Chloromethyl Ketones / metabolism*
  • Amino Acid Chloromethyl Ketones / pharmacology
  • Apoptosis
  • Caspase Inhibitors*
  • Caspases / history
  • Caspases / metabolism
  • Cysteine Proteinase Inhibitors / history
  • Cysteine Proteinase Inhibitors / metabolism
  • Drug Design
  • History, 20th Century
  • History, 21st Century
  • Humans


  • Amino Acid Chloromethyl Ketones
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Caspases