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Small‐Molecule‐Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging
Open accessAbstract
Androgen receptor (AR)‐dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts MDV3100 action from an antagonist to an agonist. Here we describe the generation of a novel class of selective androgen receptor degraders (SARDs) to address this resistance mechanism. Molecules containing hydrophobic degrons linked to small‐molecule AR ligands induce AR degradation, reduce expression of AR target genes and inhibit proliferation in androgen‐dependent prostate cancer cell lines. These results suggest that selective AR degradation may be an effective therapeutic prostate tumor strategy in the context of AR mutations that confer resistance to second‐generation AR antagonists.
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“However, molecular chaperones Hsp70 and Hsp90 can also recruit the co-chaperone E3 ligase CHIP (C-terminus of Hsp70 interacting protein), which leads to ubiquitination and degradation of the chaperone-bound client proteins [56–59].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [57]
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Metadata
- Authors
- Gustafson, J. L., Neklesa, T. K., Cox, C. S., Roth, A. G., Buckley, D. L., Tae, H. S., Sundberg, T. B., Stagg, D. B., Hines, J., McDonnell, D. P., Norris, J. D., & Crews, C. M.
- Affiliations
- Yale University (US)
- Duke University (US)
- Corresponding author
- Crews, Craig M.
- ORCID
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2015-06-17
- Volume
- 54
- Issue
- 33
- Pages
- 9659-9662
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- PMC
- PMC4547777
- OpenAlex
- W2117170436
- Cited by
- 206
- References
- 33
- Citations by year
- 2026: 20 · 2025: 23 · 2024: 17 · 2023: 22 · 2022: 22 · 2021: 15 · 2020: 23 · 2019: 18 · 2018: 17 · 2017: 16 · 2016: 11 · 2015: 1
- FWCI
- 6.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA139818)
- National Institute of General Medical Sciences (T32GM067543, F32GM10052101, F32GM100521)
- National Institute of Allergy and Infectious Diseases (R01AI084140)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- androgen receptor, protein degradation, enzalutamide resistance, androgen receptor antagonists, prostate cancer, androgen receptor agonists, small-molecule ligands, drug resistance
- MeSH terms
- Antineoplastic Agents, Benzamides, Humans, Male, Nitriles, Phenylthiohydantoin, Prostate, Prostatic Neoplasms, Receptors, Androgen, Point Mutation, Drug Resistance, Neoplasm, Cell Line, Tumor, Cell Proliferation, Small Molecule Libraries, Hydrophobic and Hydrophilic Interactions, Androgen Receptor Antagonists, Proteolysis
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