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Targeting Nuclear Receptors with PROTAC degraders
John J Flanagan1, Taavi K Neklesa2
1Arvinas, 5 Science Park, New Haven, CT, 06511, USA.
Molecular and Cellular Endocrinology
|May 25, 2019
Summary
PROTAC degraders offer a new way to block nuclear receptor (NR) signaling by degrading these proteins. This approach is advantageous over traditional antagonists for NR-targeted therapies, including for cancer treatment.
Area of Science:
- Molecular Biology
- Cellular Biology
- Pharmacology
Background:
- Nuclear receptors (NRs) are intracellular transcription factors that sense stimuli and regulate gene expression.
- NRs possess ligand-binding, DNA-binding, and regulatory domains crucial for signal transduction.
- Many approved therapeutics target NRs, highlighting their importance in disease.
Purpose of the Study:
- To introduce Proteolysis Targeting Chimeras (PROTACs) as a novel strategy for abrogating NR signaling.
- To outline functional advantages of PROTAC degraders over classical NR antagonists.
- To provide a rationale for the translational utility of NR degraders in cancer therapy.
Main Methods:
- Discussion of PROTAC technology for targeted protein degradation.
- Comparative analysis of PROTAC degraders versus ligand-binding pocket antagonists.
- Case examples focusing on Androgen Receptor and Estrogen Receptor PROTAC degraders.
Main Results:
- PROTAC degraders provide a novel mechanism to inhibit NR function by inducing protein degradation.
- Six key functional advantages of PROTAC degraders over traditional antagonists are presented.
- Specific examples illustrate the application of PROTACs for NR modulation.
Conclusions:
- PROTAC degraders represent a promising therapeutic modality for modulating NR activity.
- The degradation of Androgen Receptor and Estrogen Receptor via PROTACs shows translational potential for prostate and breast cancer treatments, respectively.
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