Bioorthogonal PROTAC Prodrugs Enabled by On-Target Activation
Mengyang Chang1, Feng Gao2, Devin Pontigon1
1Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States.
Journal of the American Chemical Society
|June 16, 2023
Summary
This study introduces click-release PROTACs (crPROTACs), a novel prodrug strategy that selectively activates proteolysis targeting chimeras in cancer cells, minimizing toxicity and enabling targeted protein degradation.
Area of Science:
- Biochemistry
- Molecular Biology
- Chemical Biology
Background:
- Proteolysis targeting chimeras (PROTACs) offer therapeutic potential but face toxicity concerns due to off-target protein degradation.
- Developing strategies for precise control over PROTAC activity is crucial for minimizing side effects.
- Cancer biomarker-activated prodrugs are being explored to enhance PROTAC selectivity.
Purpose of the Study:
- To develop a bioorthogonal, on-demand prodrug strategy for targeted PROTAC activation in cancer cells.
- To create a system for selective protein degradation in cancer cells while sparing normal cells.
- To investigate the efficacy of a click-release PROTAC (crPROTAC) approach.
Main Methods:
- Designed inactive PROTAC prodrugs (TCO-ARV-771, TCO-DT2216) by conjugating trans-cyclooctenes (TCO) to a VHL E3 ubiquitin ligase ligand.
- Utilized a tetrazine (Tz)-modified RGD peptide (c(RGDyK)-Tz) targeting the integrin αvβ3 biomarker on cancer cells for prodrug activation.
- Employed a bioorthogonal click-release mechanism for selective PROTAC activation and subsequent protein degradation.
Main Results:
- PROTAC prodrugs were selectively activated in an integrin αvβ3-dependent manner.
- Activated PROTACs effectively degraded proteins of interest (POIs) specifically within cancer cells.
- Demonstrated targeted degradation of POIs in cancer cells, distinct from noncancerous cells.
Conclusions:
- The crPROTAC strategy enables on-target activation of PROTACs, leading to selective protein degradation in cancer cells.
- This bioorthogonal approach offers a potential method for inducing cancer cell death via the ubiquitin-proteasome pathway.
- crPROTACs represent a promising abiotic strategy for targeted cancer therapy with reduced off-target effects.
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