Development of Novel Imipridones with Alkyne- and Triazole-Linked Warheads on the Tricyclic Skeleton, Showing Superior Ability to Eradicate PANC-1 and Fadu Cells Compared to ONC201

Our ongoing research focuses on the development of new imipridone derivatives. We aim to design compounds that can completely and selectively eradicate cancer cells after relatively short treatment. We have synthetized systematically designed novel hybrids and evaluated their antiproliferative activity against PANC-1 and Fadu cell lines. We have also conducted preliminary studies on the mechanism, including colony formation as well as dose-response tests in HEK293T wild-type (WT) and HEK293T CLPP^-/- cells. Following gradual structural fine-tuning based on high throughput screening, we identified two imipridone hybrids as the most potent derivatives. Their unique substitution pattern includes <i>N</i>-methylated propargylamine and ferrocenyl/phenyltriazole moieties on the benzyl groups attached to opposite sides of the imipridone core. We found that the compounds with IC₅₀ values similar to those of <b>ONC201</b> completely eradicated cancer cells at about 4 μM, while <b>ONC201</b> treatment at even higher concentrations left 30-50% of viable cells behind. Both compounds exerted equal activity in WT and CLPP^-/- HEK293T cells, indicating a ClpP-independent mechanism. Further development is needed to improve the tumor selectivity of the two potent imipridone derivatives. By preserving tumor cytotoxicity, we aim to generate new drug candidates that evade resistance and can be applied in a sufficiently broad therapeutic window.