Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize...

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• The human mitochondrial ClpXP protease complex (HsClpXP) is a potential anti-cancer target, but its cellular functions are not well understood.
• Few small molecule inhibitors for HsClpXP have been identified, limiting therapeutic development.

Purpose of the Study:

• To screen existing bacterial ClpXP inhibitors for activity against human ClpXP.
• To investigate the anti-cancer potential and mechanism of action of identified inhibitors.

Main Methods:

• Screening of Staphylococcus aureus ClpXP inhibitors against human ClpXP.
• Testing hit compounds for anti-cancer activity in various cancer cell lines (leukemia, liver, breast).
• Investigating the effects of inhibitor 334 on the electron transport chain, mitochondrial ROS production, proteostasis, and apoptosis.

Main Results:

• Potent small molecule inhibitors of human ClpXP were identified.
• Hit compounds demonstrated anti-cancer activity across multiple cancer cell lines.
• Bacterial ClpXP inhibitor 334 impaired the electron transport chain, increased mitochondrial ROS, and induced apoptosis.
• Compound 334 showed efficacy in patient-derived leukemia cells and enhanced chemotherapy effects.

Conclusions:

• Small molecules targeting HsClpXP are promising anti-cancer agents.
• Inhibitor 334 exhibits a multi-faceted anti-cancer mechanism involving mitochondrial dysfunction and proteostasis disruption.
• HsClpXP inhibitors have potential for treating resistant cancers and potentiating existing therapies.