PAC‐1: A novel therapeutic approach to procaspase activation

Abstract

The recent emergence of proapoptotic small molecules as powerful anti‐cancer agents allows for the direct induction of apoptotic pathways. Central to these pathways is the activation of executioner caspases responsible for the proteolysis of a host of cellular substrates. This vital role presents caspases as a promising new target in the search for new chemotherapeutic agents.In a screen for small molecule activators of procaspase‐3, a novel compound, PAC‐1, was identified [Nature Chem. Biol. 2006, 2, 543]. The compound was shown to activate procaspase‐3 to caspase‐3 in vitro, kill cancer cells in culture and inhibit tumor growth in mouse xenograft models. Current work has elucidated the in vitro mechanism of action of PAC‐1 mediated activation of procaspase‐3, and has explored the effect of metal ions on procaspase activation. In addition, to further investigate the PAC‐1 mechanism of action we synthesized several derivatives to probe the structure‐activity relationship of this family of compounds. The ability of these derivatives to activate PAC‐1 sheds further light on the PAC‐1 mechanism of action and suggests means for the chemical optimization of this anti‐cancer agent.