The androgen receptor (AR) is a nuclear receptor that is the primary therapeutic target of prostate cancer (CaP). This grant concerns characterization of a cellular pathway that regulates AR activity, which could produce new therapeutic targets, and the application of a novel screening strategy to identify small molecules that inhibit AR function. We hypothesize that the Rho/ROCK/LIM kinase (RRL) pathway regulates AR activity through alterations in the actin cytoskeleton. I will use prostate carcinoma lines that stably express native and fluorescently-labeled AR to determine how the RRL pathway influences the folding, dimerization, nuclear import, and transcriptional activity of AR. We also hypothesize that compounds that inhibit AR ligand-induced conformational change may reveal novel anti-androgens that would be missed by traditional screens for AR inhibitors. I will use a high-throughput FRET assay to screen three collections of biologically active small molecules for compounds that inhibit AR ligand-induced conformational change. The most effective inhibitors will be examined in detailed secondary analyses to determine their effect on AR nuclear transport, dimerization, native AR-responsive transcription, and proliferation of prostate cancer cells. ? ? ? ?
| Kim, W; Jones, J O; Diamond, M et al. (2014) Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with abiraterone acetate. Prostate Cancer Prostatic Dis 17:292-9 |
| Jones, Jeremy O; An, W Frank; Diamond, Marc I (2009) AR inhibitors identified by high-throughput microscopy detection of conformational change and subcellular localization. ACS Chem Biol 4:199-208 |
| Jones, Jeremy O; Diamond, Marc I (2008) A cellular conformation-based screen for androgen receptor inhibitors. ACS Chem Biol 3:412-8 |
