biostudies-literatureXu ZNIH HHS21377-21393https://www.ebi.ac.uk/biostudies/studies/S-EPMC12700136biostudies-literatureUnknown68(20)Cancer cells depend on mitochondrial reprogramming for growth, but this raises reactive oxygen species (ROS), increasing reliance on protein quality control (PQC) repair mechanisms. The mitochondrial proteome is maintained through a robust PQC composed of chaperones and proteases, including the mitochondrial matrix protease caseinolytic protease P (ClpP). ClpP has recently emerged as a potential therapeutic target against cancer. Notably, imipridones act as ClpP agonists and have shown potent anticancer activity by inhibiting mitochondrial Electron Transport Chain (ETC) function. In this study, we developed a new generation ClpP agonist, compound <b>9</b> (MS6076), which exhibits enhanced ClpP binding, more potent disruption of mitochondrial ETC and lethality in breast cancer models compared to the imipridone ONC212. Furthermore, we show that compound <b>9</b> induced cell death in cancer cells resistant to ONC212. The discovery and characterization of compound <b>9</b> therefore add to the expanding arsenal of imipridones to target ClpP in cancer.Journal of medicinal chemistryTargeting the Mitochondrial Protease ClpP for Anticancer Therapy.PMC12700136S10 OD025132S10 OD028504Germain DChattopadhyay MKaniskan HUPokushalov DChoo CLee YKabir MJin JXu ZJenkins ECfalseTargeting the Mitochondrial Protease ClpP for Anticancer Therapy.Cancer cells depend on mitochondrial reprogramming for growth, but this raises reactive oxygen species (ROS), increasing reliance on protein quality control (PQC) repair mechanisms. The mitochondrial proteome is maintained through a robust PQC composed of chaperones and proteases, including the mitochondrial matrix protease caseinolytic protease P (ClpP). ClpP has recently emerged as a potential therapeutic target against cancer. Notably, imipridones act as ClpP agonists and have shown potent anticancer activity by inhibiting mitochondrial Electron Transport Chain (ETC) function. In this study, we developed a new generation ClpP agonist, compound <b>9</b> (MS6076), which exhibits enhanced ClpP binding, more potent disruption of mitochondrial ETC and lethality in breast cancer models compared to the imipridone ONC212. Furthermore, we show that compound <b>9</b> induced cell death in cancer cells resistant to ONC212. The discovery and characterization of compound <b>9</b> therefore add to the expanding arsenal of imipridones to target ClpP in cancer.2025-01-01T00:00:00Z2025 Oct2026-06-06T02:16:31.053Z2026-05-24T03:12:18.199ZS-EPMC127001364103269010.1021/acs.jmedchem.5c01315