Targeting human caseinolytic protease P (ClpP) as a novel therapeutic strategy in ovarian cancer

Ovarian cancer (OC) is currently one of the most life-threatening types of gynecological malignancy with limited treatment options and poor clinical outcomes. Human caseinolytic protease P (HsClpP) is located in the mitochondria and plays an important role in several tumors. Moreover, HsClpP is overexpressed in OC and several other tumor cells. Thus, HsClpP modulation is regarded as a potential approach for OC treatment. In this study, we identified and validated a novel boron peptide Compound 43-8F as a potent HsClpP inhibitor. Upon 43-8F treatment, mitochondrial damage was observed to be closely correlated with upregulated intracellular reactive oxygen species production, decreasement of membrane potential, and ATP content suppression. Meanwhile, the expression level of SDHB and the ATF4 was increased after 43-8F treatment, suggesting that 43-8F treatment induces mitochondrial respiratory disorders and activates the integrated stress response pathway to inhibit tumor cell growth. Further, 43-8F exhibited a good therapeutic and safety profile in OC xenograft model in nude mice. Together, these results suggest that 43-8F exerts an anti-ovarian cancer effect by inhibiting HsClpP pathway.