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Updated: Feb 27, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by
Khalid Z Masoodi1,2, Yadong Xu1,3,4, Javid A Dar1,5
1Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Abstract:
The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes. A key step in androgen action, which is amplified in castration-resistant prostate cancer (CRPC), is AR nuclear translocation. Small molecules capable of inhibiting AR nuclear localization could be developed as novel therapeutics for CRPC. We developed a high-throughput screen and identified two structurally-related pyrroloimidazoles that could block AR nuclear localization in CRPC cells. We show that these two small molecules, 3-(4-ethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (EPPI) and 3-(4-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (CPPI) can inhibit the nuclear localization and transcriptional activity of AR and reduce the proliferation of AR-positive but not AR-negative prostate cancer cell lines. EPPI and CPPI did not inhibit nuclear localization of the glucocorticoid receptor or the estrogen receptor, suggesting they selectively target AR. In LNCaP tumor xenografts, CPPI inhibited the proliferation of relapsed LNCaP tumors. These findings suggest that EPPI and CPPI could serve as lead structures for the development of therapeutic agents for CRPC. Mol Cancer Ther; 16(10); 2120-9. ©2017 AACR.
Insights
Two novel pyrroloimidazole compounds, EPPI and CPPI, effectively block androgen receptor (AR) nuclear translocation in prostate cancer cells. These compounds show potential as new therapeutics for castration-resistant prostate cancer (CRPC).
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Androgen receptor (AR) nuclear translocation is crucial for androgen action and amplified in castration-resistant prostate cancer (CRPC).
- Targeting AR nuclear localization offers a potential therapeutic strategy for CRPC.
Purpose of the Study:
- To identify small molecules that inhibit AR nuclear translocation.
- To evaluate the efficacy of identified compounds in preclinical models of prostate cancer.
Main Methods:
- High-throughput screening to identify AR nuclear localization inhibitors.
- In vitro assays using prostate cancer cell lines to assess AR activity and proliferation.
- In vivo studies using LNCaP tumor xenografts.
Main Results:
- Two pyrroloimidazole compounds, EPPI and CPPI, were identified that inhibit AR nuclear translocation and transcriptional activity.
- EPPI and CPPI reduced proliferation in AR-positive prostate cancer cells but not AR-negative cells.
- CPPI demonstrated efficacy in inhibiting LNCaP tumor xenograft proliferation.
Conclusions:
- EPPI and CPPI selectively inhibit AR nuclear localization and activity.
- These compounds represent promising lead structures for developing novel CRPC therapeutics.
- Targeting AR nuclear translocation is a viable strategy for CRPC treatment.
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