caseinolytic protease P (ClpP) is essential for maintaining mitochondrial proteome homeostasis, and its activation is increasingly recognized as a promising cancer therapy strategy. Herein, based on structure-guided drug design, we discovered a series of potent ClpP activators by introducing a methyl group to the imipridone scaffold of the ClpP activator in Phase III clinical trials. Through structural optimization of the lead compound, the most optimal compound, , exhibited exceptionally potent ClpP agonistic activity (EC = 23.5 nM, 107.1-fold stronger than ) and inhibited the proliferation of HL60 cells (IC = 4.6 nM, 169.2-fold stronger than ). possesses good pharmacokinetic properties and effectively prolongs the lifespan in the MOLM13 and HL60 xenograft models in mice through oral administration. is the most potent and orally efficacious ClpP activator reported to date.