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Development of an aryl hydrocarbon receptor antagonist using the proteolysis-targeting chimeric molecules approach: a
Dinesh Puppala1, Hyosung Lee, Kyung Bo Kim
1Department of Molecular and Biomedical Pharmacology, MS305, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY40536, USA.
Abstract:
Activation of the aryl hydrocarbon receptor (AHR) by agonists and environmental contaminants like dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) leads to many adverse biological effects, including tumor promotion. With this in mind, we propose that agents that block the AHR pathway may be therapeutically beneficial, particularly by exhibiting chemopreventive activities. In our current research, we have focused on the development of an AHR antagonist using a chemical genetic approach called PROTACS (PROteolysis-TArgeting Chimeric moleculeS). PROTACS is a novel approach of tagging small recognition sequences of a specific E3 ubiquitin ligase complex to a known ligand for the receptor of interest (AHR) for targeting its degradation. Here, we present the design and initial characterization of AHR targeting PROTACS (Apigenin-Protac) designed to degrade and inhibit the AHR in epithelial cells. Our results demonstrate the "proof of concept" of this approach in effectively blocking AHR activity in cultured cells.
Insights
New PROTACs (Proteolysis-Targeting Chimeric molecules) degrade the aryl hydrocarbon receptor (AHR), offering potential chemopreventive therapies. This approach targets AHR antagonists for tumor promotion inhibition.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Aryl hydrocarbon receptor (AHR) activation by agonists and contaminants like dioxin causes adverse effects, including tumor promotion.
- Blocking the AHR pathway presents a potential therapeutic strategy for chemoprevention.
Purpose of the Study:
- To develop and characterize AHR-targeting PROTACs (Proteolysis-Targeting Chimeric molecules) as antagonists.
- To demonstrate the efficacy of PROTACs in degrading and inhibiting AHR in epithelial cells.
Main Methods:
- Utilized a chemical genetic approach using PROTACs to target AHR for degradation.
- Designed Apigenin-Protac, an AHR-targeting PROTAC, for use in epithelial cells.
- Performed initial characterization of the PROTAC's activity in cell cultures.
Main Results:
- Successfully designed and synthesized an AHR-targeting PROTAC (Apigenin-Protac).
- Demonstrated the "proof of concept" for PROTAC-mediated AHR degradation and inhibition.
- Confirmed effective blocking of AHR activity in cultured epithelial cells.
Conclusions:
- PROTAC technology offers a novel strategy for developing AHR antagonists.
- Apigenin-Protac effectively degrades and inhibits AHR, supporting its potential as a chemopreventive agent.
- This approach shows promise for therapeutic intervention in AHR-mediated diseases.
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