Cited by 216Protein Degradation and InhibitorsProstate Cancer Treatment and ResearchChemical Synthesis and Analysis

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Small‐Molecule‐Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging

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Gustafson, Jeffrey L., Neklesa, Taavi K., Cox, Carly S., Roth, Anke G., Buckley, Dennis L., Tae, Hyun Seop, Sundberg, Thomas B., Stagg, D. Blake, Hines, John, McDonnell, Donald P., Norris, John D., Crews, Craig M.·2015·Angewandte Chemie International Edition

DOI 10.1002/anie.201503720PMC PMC4547777

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Abstract

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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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: Gustafson, Jeffrey L.
Neklesa, Taavi K.
Buckley, Dennis L.
Sundberg, Thomas B.
Stagg, D. Blake
McDonnell, Donald P.
Norris, John D.
Crews, Craig M.
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
DOI: 10.1002/anie.201503720
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
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
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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Small‐Molecule‐Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging

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