Direct Procaspase-3 Activation as an Anti-Cancer Strategy: Compound Discovery, Mechanism of Action, and a Canine Clinical Trial
Abstract for lecture: Despite tremendous advances in cell biology and medicinal chemistry, the entirety of FDA-approved drugs target just ~300 different human proteins. While the development of new compounds for known targets has value, large advances in disease treatment are likely to come from the exploitation of new biological targets. A major goal of my laboratory is to identify novel targets and compounds for the treatment of cancer, with an eye toward personalized therapeutics that can be matched with specific defects in the cancerous cells of a patient. In this lecture the direct activation of procaspase-3 as a novel anti-cancer strategy will be detailed. The discovery of the first procaspase-3 activating compound (PAC-1), the biochemical mode of action of PAC-1, the chemical optimization of PAC-1, and the mechanism by which PAC-1 induces death in cancer cells in culture will all be described. In addition, the beginnings of a clinical trial of a PAC-1 derivative in client-owned dogs (pets) with lymphoma will be reported.