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Targeting the Mitochondrial Protease ClpP for Anticancer Therapy.

Zhongli Xu1, Dmitry Pokushalov2, Md Kabir1

  • 1Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

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A new compound targeting caseinolytic protease P (ClpP) shows potent anticancer activity by disrupting mitochondrial function. This ClpP agonist is effective against resistant cancer cells, offering a promising therapeutic strategy.

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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.