Discovery of\nCLPP-1071 as an Exceptionally Potent\nand Orally Efficacious Human ClpP Activator with Strong In Vivo Antitumor\nActivity

Human sapiens caseinolytic\nprotease\nP (ClpP) is essential for maintaining mitochondrial proteome homeostasis,\nand its activation is increasingly recognized as a promising cancer\ntherapy strategy. Herein, based on structure-guided drug design, we\ndiscovered a series of potent ClpP activators by introducing a methyl\ngroup to the imipridone scaffold of the ClpP activator <b>ONC201</b> in Phase III clinical trials. Through structural optimization of\nthe lead compound, the most optimal compound, <b>CLPP-1071</b>, exhibited exceptionally potent ClpP agonistic activity (EC<sub>50</sub> = 23.5 nM, 107.1-fold stronger than <b>ONC201</b>)\nand inhibited the proliferation of HL60 cells (IC<sub>50</sub> = 4.6\nnM, 169.2-fold stronger than <b>ONC201</b>). <b>CLPP-1071</b> possesses good pharmacokinetic properties and effectively prolongs\nthe lifespan in the MOLM13 and HL60 xenograft models in mice through\noral administration. <b>CLPP-1071</b> is the most potent and\norally efficacious ClpP activator reported to date.