Related Experiment Video
Updated: Apr 9, 2026
High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging
Jeffrey L Gustafson1, Taavi K Neklesa1, Carly S Cox1
1Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA).
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.
Insights
Researchers developed novel selective androgen receptor degraders (SARDs) to overcome resistance to prostate cancer drugs like enzalutamide. These SARDs degrade the androgen receptor (AR), offering a new therapeutic strategy for resistant prostate tumors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Androgen receptor (AR) signaling drives prostate tumor cell proliferation.
- AR antagonists like enzalutamide are key chemotherapeutic agents.
- AR mutations, such as F876L, can cause resistance by converting antagonists into agonists.
Purpose of the Study:
- To develop a novel therapeutic strategy to overcome AR-mediated resistance to anti-androgen drugs.
- To generate a new class of molecules targeting AR degradation.
Main Methods:
- Design and synthesis of selective androgen receptor degraders (SARDs).
- Molecules were engineered with hydrophobic degrons linked to AR ligands.
- Evaluation of SARDs in androgen-dependent prostate cancer cell lines.
Main Results:
- SARDs successfully induced AR degradation.
- Reduced expression of AR target genes was observed.
- Inhibition of proliferation in prostate cancer cell lines was achieved.
Conclusions:
- Selective AR degradation is a promising therapeutic approach for prostate cancer.
- SARDs offer a potential strategy against AR mutations conferring resistance to current therapies.
More Related Videos
14:02Optimizing the Genetic Incorporation of Chemical Probes into GPCRs for Photo-crosslinking Mapping and Bioorthogonal Chemistry in Live Mammalian Cells
Published on: April 9, 2018
16:16Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors
Published on: September 13, 2013
Related Concept Videos
02:58Regulated Protein Degradation
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
01:12GPCR Desensitization
01:31Internal Receptors
01:13The Proteasome
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
02:18The Proteasome
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...