Therapeutics: Procaspase-3; caspase-3 (CASP3; CPP32)

In vitro and mouse studies suggest metabolically stable analogs of procaspase-activating compound 1 (PAC-1) could help treat cancer. PAC-1 converts procaspase-3 to CASP3 to induce cell death, but its rapid degradation via multiple oxidation pathways limits its in vivo efficacy. Screening and in vitro testing of a select library of hydrazide- and aldehyde-based PAC-1 analogs that lacked the oxidizable functional groups identified four lead compounds that activated procaspase-3 with comparable potency to PAC-1. In rat liver microsomes, two of the lead compounds were more stable than PAC-1. In mice, all four lead compounds had longer serum half-lives and three had greater AUCs and oral availability. Next steps include testing the compounds in animal models of cancer...