Imipridones Target Mitochondrial Function In Cells

According to the scientific research study showing that; imipridones target mitochondrial function in cancer cells. This demonstrating that members of the imipridone family; ONC201 and ONC212 directly activate a mitochondrial protease called caseinolytic protease P (ClpP). Demonstrates that ONC201 and ONC212 hyperactivate ClpP by altering its structural conformation, leading to mitochondrial dysfunction and apoptosis in leukemia.

In AML, ClpP is over-expressing in patient samples; and its hyperactivation selectively kills cancer cells independent of p53 status; while not affecting normal cells. ClpP is a protease located in the mitochondrial matrix that is overexpressed in tumor cells; and plays a central role in mitochondrial protein quality control by degrading misfolded proteins.

Modulating the activity of ClpP can cause impaired oxidative phosphorylation; that selectively kills cancer cells in vitro and in vivo without affecting normal cells. The two research studies concordantly demonstrate that imipridones are capable of targeting ClpP in tumor cells; which has emerged as a therapeutic target in oncology.

Mitochondrial function in cells

But ClpP activation by imipridones is consistent with select downstream effects; of these compounds that have been previously reported, such as integrated stress response activation and disruption of mitochondrial structure and function in tumor cells. The unique phenotypic effects of ONC201 and its imipridone family members that have been studied in a broad range of cancers point to a novel mechanism of action.

The discovery that ONC201 targets ClpP, in addition to DRD2, expands the biomarker panel for the molecule and other impridones. ClpP activation also helps us interpret downstream effects of imipridones on the mitochondria, as well as their activity in tumor types beyond those that depend on the dopamine pathway.

Degrading misfolded proteins

ClpP is a protease locating in the mitochondrial matrix; that is overexpressing in tumor cells and playing a central role in mitochondrial protein quality control by degrading misfolded proteins. Modulating the activity of ClpP can cause impaired oxidative phosphorylation that selectively kills cancer cells in vitro and in vivo without affecting normal cells.

The discovery that ONC201 targets ClpP, in addition to DRD2, expands the biomarker panel for the molecule and other impridones. But ClpP activation in cancer and disruption of the resulting mitochondrial dysfunction by ONC201; provides a mechanism of action that reinforces the basis for its efficacy spectrum across cancer that differentiates from other DRD2 antagonists,” said Dr. Keith Flaherty, MD, Director of Clinical Research at Massachusetts General Hospital and Member of Oncoceutics