Targeting the Mitochondrial Protease ClpP for Anticancer Therapy

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Cancer cells require mitochondrial reprogramming for growth, leading to increased reactive oxygen species (ROS) and dependence on protein quality control (PQC).
• The mitochondrial proteome relies on PQC mechanisms, including the caseinolytic protease P (ClpP), a potential cancer therapeutic target.

Purpose of the Study:

• To develop and characterize a novel ClpP agonist with enhanced anticancer properties.
• To evaluate the efficacy of the new compound against breast cancer models, including those resistant to existing therapies.

Main Methods:

• Development of a new generation ClpP agonist, compound 9 (MS6076).
• Assessment of compound 9's binding affinity to ClpP.
• Evaluation of compound 9's impact on mitochondrial Electron Transport Chain (ETC) function and cancer cell lethality.
• Testing compound 9 in cancer cells resistant to the imipridone ONC212.

Main Results:

• Compound 9 demonstrated enhanced ClpP binding compared to ONC212.
• Compound 9 more potently disrupted mitochondrial ETC function and induced lethality in breast cancer models.
• Compound 9 effectively induced cell death in cancer cells exhibiting resistance to ONC212.

Conclusions:

• Compound 9 represents a potent, next-generation ClpP agonist with significant anticancer activity.
• The findings support the therapeutic potential of imipridones targeting ClpP for cancer treatment, including overcoming drug resistance.