Understanding and Improving the Membrane Permeability of VH032-Based PROTACs
Victoria G Klein1, Chad E Townsend1, Andrea Testa2
1Department of Chemistry and Biochemistry, University of California Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States.
ACS Medicinal Chemistry Letters
|September 17, 2020
Summary
We developed a new method to assess the permeability of Proteolysis targeting chimeras (PROTACs). This approach provides insights into PROTAC structure-permeability relationships for designing more effective degraders.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Drug Discovery
Background:
- Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that induce targeted protein degradation.
- Most PROTACs exhibit poor membrane permeability, limiting their therapeutic potential.
- Understanding PROTAC structure-permeability relationships is crucial for designing effective drugs.
Purpose of the Study:
- To develop and validate a label-free method for assessing PROTAC permeability.
- To investigate the structure-permeability relationships of VH032-based PROTACs.
- To establish a framework for predicting PROTAC physicochemical properties.
Main Methods:
- Utilized a parallel artificial membrane permeability assay (PAMPA).
- Employed a lipophilic permeability efficiency (LPE) metric.
- Combined PAMPA and LPE for a comprehensive cell-free permeability assessment.
Main Results:
- The developed method successfully assessed the permeability of VH032-based PROTACs and their components.
- New insights into PROTAC structure-permeability relationships were obtained.
- The study provides a conceptual framework for predicting PROTAC properties.
Conclusions:
- The combination of PAMPA and LPE offers a valuable tool for evaluating PROTAC permeability.
- This approach can guide the design of more permeable and effective PROTAC degraders.
- Further development of PROTACs can benefit from understanding these structure-permeability correlations.
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