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Dose Optimization of ClpP Agonists Using an In Vitro Microfluidic Perfusion Platform and In Silico
Ronald W Bucher1, Lee M Graves2, Derek W Bartlett3
1Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
The AAPS Journal
|June 13, 2025
Summary
Small molecule ClpP agonists disrupt cancer metabolism. An animal-alternative platform predicts anti-tumor efficacy by correlating cell proliferation with drug exposure duration and concentration, guiding cancer therapeutic development.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Small molecule activators of mitochondrial caseinolytic protease P (ClpP agonists) target tumor metabolism.
- ONC201, an imipridone ClpP agonist, is in clinical trials; analogs are in preclinical development.
- Previous studies showed a unique, prolonged pharmacokinetic-pharmacodynamic (PK-PD) relationship for ONC201 in mice, influencing human dosing strategies.
Purpose of the Study:
- To systematically analyze PK-PD relationships for ClpP agonists.
- To define the optimal exposure profile for ClpP agonists as cancer therapeutics.
- To validate an animal-alternative platform for translational PK-PD studies of ClpP agonists.
Main Methods:
- Combined PK-PD modeling with a microfluidic perfusion platform.
- Assessed anti-proliferative effects on triple-negative breast cancer cells.
- Validated PK-PD model predictions in a mouse tumor xenograft study.
Main Results:
- Anti-proliferative effects correlated with the magnitude and duration of ClpP agonist exposure above a ClpP activation threshold.
- PK-PD model simulations using microfluidic data successfully predicted in vivo anti-tumor efficacy.
- Demonstrated translational relevance of the in vitro PK-PD platform.
Conclusions:
- The microfluidic platform provides a viable animal-alternative for translational PK-PD studies of ClpP agonists.
- This approach can guide dose optimization for ClpP agonists in cancer therapy.
- Understanding PK-PD relationships is crucial for developing effective ClpP agonist cancer treatments.
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