Discovery of a Novel Series of Imipridone Compounds as Homo sapiens Caseinolytic Protease P Agonists with Potent Antitumor Activities In Vitro and In Vivo

Abstract

<i>Homo sapiens</i> caseinolytic protease P (HsClpP) plays an important role in maintaining mitochondrial proteostasis. Activating HsClpP has been proved to be a potential strategy for cancer therapy. In this paper, a novel class of HsClpP agonists is designed and synthesized using a position shift strategy based on the imipridone <b>ONC201</b>. Among these newly synthesized imipridone derivatives, compound <b>16z</b> exhibits remarkably enhanced antitumor activity (IC₅₀ = 0.04 μM against HCT116 cells). It can improve HsClpP thermal stability and induce mitochondrial dysfunction, reactive oxygen species production, cell cycle arrest in the G0/G1 phase, and apoptosis of HCT116 cells. Moreover, compound <b>16z</b> possesses excellent pharmacokinetic profiles and significantly inhibits tumor growth in HCT116 cell-inoculated xenograft nude mouse models. Our study demonstrates that <b>16z</b> has potential to be an antitumor drug candidate for further development and provides insights for the design of the next generation of HsClpP agonists for cancer treatment.