Cell-ELISA-Based High-Throughput Screening Leads to the Discovery of Androgen Receptor Degraders to Conquer
Yang Ji1,2, Meng Wu3, Haojia Dong1,2
1Department of Biology, Zhejiang Normal University, Jinhua, P. R. China.
Abstract:
Androgen receptor (AR) antagonists play a pivotal role in the treatment of castration-resistant prostate cancer (CRPC). However, the reactivation of AR signaling during antiandrogen therapy remains a major factor contributing to resistance against currently used clinical antagonists. As a result, strategies aimed at degrading the AR protein have garnered substantial attention for CRPC therapy. In this study, we first established a high-throughput screening (HTS) model for AR degraders based on Cell-ELISA technology. Using this model to screen our in-house chemical database, we identified a novel AR degrader, ZC9. Functional evaluations demonstrated that ZC9 exhibits significant inhibitory activity against CRPC cell proliferation and effectively downregulates AR protein levels. Mechanistic studies revealed that ZC9 directly binds to AR and inhibits dihydrotestosterone (DHT)-induced nuclear translocation of AR. Furthermore, ZC9 promotes AR degradation via the ubiquitin-proteasome system (UPS) and suppresses AR transcriptional activity. Collectively, these findings highlight ZC9 as a promising lead compound for the treatment of CRPC.
Insights
A novel compound, ZC9, effectively degrades androgen receptor (AR) protein, offering a promising strategy to overcome resistance in castration-resistant prostate cancer (CRPC) treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Androgen receptor (AR) antagonists are crucial for castration-resistant prostate cancer (CRPC) treatment.
- AR signaling reactivation drives resistance to current antiandrogen therapies.
- AR protein degradation is a key therapeutic strategy for CRPC.
Purpose of the Study:
- To develop a high-throughput screening (HTS) model for identifying AR degraders.
- To identify and characterize novel AR degraders for CRPC therapy.
Main Methods:
- Established a Cell-ELISA based HTS model for AR degrader screening.
- Screened an in-house chemical database to identify AR degraders.
- Conducted functional evaluations and mechanistic studies on the identified compound.
Main Results:
- Identified ZC9 as a novel AR degrader.
- ZC9 demonstrated significant inhibition of CRPC cell proliferation and AR protein downregulation.
- ZC9 directly binds AR, inhibits DHT-induced nuclear translocation, and promotes AR degradation via the ubiquitin-proteasome system (UPS).
- ZC9 suppressed AR transcriptional activity.
Conclusions:
- ZC9 is a potent AR degrader with significant anti-cancer activity against CRPC.
- ZC9 shows promise as a lead compound for developing new CRPC therapeutics.
