Targeting 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 9 (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 9 induced
cell death in cancer cells resistant to ONC212. The discovery and
characterization of compound 9 therefore add to the expanding
arsenal of imipridones to target ClpP in cancer.