Selective activator of mitochondrial ClpP suppresses lung squamous cell carcinoma

Targeting the mitochondrial caseinolytic protease P (ClpP) is a potential novel strategy for treating cancer. However, little is known about the therapeutic effects of ClpP in lung squamous cell carcinoma (LUSC) and no potent and selective activator has been reported. In this study, we report on the first highly selective and potent activator for mitochondrial ClpP, ZK53, showing a negligible effect on bacterial ClpP. ZK53 features on a scaffold with flexible configuration. ZK53-bound ClpP degrades the electron transport chain in lung squamous cell carcinoma cells in a mitochondrial ClpP-dependent manner, leading to cell cycle arrest eventually. Also, ZK53 exhibits therapeutic antitumor effects in the xenografted mice model.