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

Based on the founding member of imipridones, ONC201, 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, XT6, 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, XT6 exhibited a promising
pharmacokinetic profile in rats and could penetrate the blood brain
barrier. It showed highly potent in vivo antitumor
activity in a MIAPACA2 cell line derived pancreatic cancer model in
BALB/c nude mice.