Recent advances in the design of small molecules targeting human ClpP.

Human mitochondrial ClpP (hClpP), a pivotal protease regulating mitochondrial protein homeostasis, has emerged as an important target for anticancer drug development. In recent years, significant progress has been made in designing small molecules targeting hClpP, primarily classified into activators and inhibitors. Activators specifically stimulate ClpP proteolytic activity by mimicking the mechanism of its chaperone protein ClpX, with representative compounds, such as imipridone derivatives (ONC201/206/212) and their optimized products (ZK53, 7k, etc.) demonstrating excellent antitumor efficacy. Investigation of their structural design and pharmacological properties provides theoretical insights for subsequent drug development. Significant progress has been made in agonist research, and although there are still issues that need to be addressed, hClpP-targeted drugs hold promise as new therapies for the treatment of cancer.