Inhibition of androgen independent prostate cancer cells by small molecules

摘要: AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 1315 Hormone-refractory prostate cancer (HRPC) although does not require androgen for growth is still often dependent on the activity of Androgen Receptor (AR), which becomes functional in absence natural ligand androgen. We hypothesized that inhibition AR pathway would be effective way PC even refractory stage disease. The aim our work to find inhibitors active against HRPC. Methods: CWR22RV1 cells were chosen as a model independent PC. reporter system consisting luciferase under control promoter was used readout assay screening small molecules capable inhibiting activity. 34K molecule library selection primary hits. following assays run exclude non-specific and false-positive hits: (i) transcription factors, other than AR, including several nuclear receptors, (ii) expression endogenous targets (PSA), (iii) effect panel non-prostate tumor cell lines. Results: have selected compounds, belonging different chemical classes, effectively inhibit transactivation function are specifically toxic vitro . Interestingly among best hits we able distinguish two subgroups, one cause rather quick death (1-3 days) another causing slow mostly resulting arrest. Looking molecular mechanism compounds toxicity found chemicals first group disappearance protein while “slow” do affect expression. Computer modelling allowed us propose second interferes with AR-DNA binding. Experiments testing this hypothesis will performed changes gene caused by both compared suppression siRNA Conclusion: Specific been isolated development new type drug androgen-refractory