Homo sapiens 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 ONC201. Among these newly synthesized imipridone derivatives, compound 16z 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 16z possesses excellent pharmacokinetic profiles and significantly inhibits tumor growth in HCT116 cell-inoculated xenograft nude mouse models. Our study demonstrates that 16z 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.