
Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.
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.
Duke Scholars
Altmetric Attention Stats
Dimensions Citation Stats
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Small Molecule Libraries
- Receptors, Androgen
- Proteolysis
- Prostatic Neoplasms
- Prostate
- Point Mutation
- Phenylthiohydantoin
- Organic Chemistry
- Nitriles
- Male
Citation

Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Small Molecule Libraries
- Receptors, Androgen
- Proteolysis
- Prostatic Neoplasms
- Prostate
- Point Mutation
- Phenylthiohydantoin
- Organic Chemistry
- Nitriles
- Male