Inhibition of Androgen Receptor Nuclear Localization and Castration Resistant Prostate Tumor Growth by Pyrroloimidazole-Based Small Molecules

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.

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