Oncoceutics, Inc. announced the publication of two scientific research articles demonstrating that members of the imipridone family ONC201 and ONC212 directly activate a mitochondrial protease called caseinolytic protease P (ClpP).
One research article, featured on the cover of the journal Cancer Cell, 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-expressed in patient samples and its hyperactivation selectively kills cancer cells independent of p53 status, while not affecting normal cells.
Another research article, published in the journal ACS Chemical Biology, similarly demonstrates that ONC201 and ONC212 directly bind to and activate ClpP.
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. 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.”
Dr. Joshua Allen, PhD, Senior Vice President of R&D at Oncoceutics
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.”
Dr. Keith Flaherty, MD, Director of Clinical Research at Massachusetts General Hospital and Member of Oncoceutics’ Scientific Advisory Board