Discovery of Dehydrogenated Imipridone Derivatives as Activators of Human Caseinolytic Protease P

Based on the founding member of imipridones, <b>ONC201</b>, a class of dehydrogenated imipridone derivatives was designed, synthesized, and evaluated in a series of biochemical and biological assays as human caseinolytic protease P (hClpP) activators. Mechanism studies for one of the most potent compounds, <b>XT6</b>, indicated that it can potently bind to both recombinant and cellular hClpP, effectively promote the formation of hClpP tetradecamer, efficiently induce the degradation of hClpP substrates, robustly upregulate the expression of ATF4, and strongly inhibit the phosphorylations of AKT and ERK. More importantly, <b>XT6</b> exhibited a promising pharmacokinetic profile in rats and could penetrate the blood brain barrier. It showed highly potent <i>in vivo</i> antitumor activity in a MIAPACA2 cell line derived pancreatic cancer model in BALB/c nude mice.