Discovery of CLPP-1071 as an Exceptionally Potent and Orally Efficacious Human ClpP Activator with Strong In Vivo Antitumor Activity.

Human sapiens 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 ONC201 in Phase III clinical trials. Through structural optimization of the lead compound, the most optimal compound, CLPP-1071, exhibited exceptionally potent ClpP agonistic activity (EC(50) = 23.5 nM, 107.1-fold stronger than ONC201) and inhibited the proliferation of HL60 cells (IC(50) = 4.6 nM, 169.2-fold stronger than ONC201). CLPP-1071 possesses good pharmacokinetic properties and effectively prolongs the lifespan in the MOLM13 and HL60 xenograft models in mice through oral administration. CLPP-1071 is the most potent and orally efficacious ClpP activator reported to date.