Inverse Agonists of the Androgen Receptor

We report the efficacy of androgen receptor inverse agonists (ARIAs) in altering androgen receptor (AR) transcriptional activity. Through RNA-sequencing studies in a panel of prostate cancer cell lines and patient derived xenograft models, we demonstrate ARIAs succcessfully inhibit androgen response gene sets. ChIP-seq and CUT&RUN studies demonstrate H3K27ac decreases at AR-target genes in response to treatment. AR and NCOR1/2 localizes at these regions of acetylation loss. HiChIP further revealed loss of 3D connectivity in reponse to ARIA treatment, RNA-seq studies of prostate cancer (PCa) cell lines or patient derived xenograft models treated with controls or androgen receptor inverse agonists (ARIA). CUT&RUN or ChIP-seq with control or ARIA treatment in PCa cell lines with IP targets including AR, H3K27ac, NCOR1, and NCOR2/SMRT. HiChIP with control or ARIA treatment in PCa cell lines with IP targets of AR, H3K27ac, and CTCF.