Rational design of novel antiandrogens for neutralizing androgen receptor function in hormone refractory prostate cancer

BACKGROUND. The standard hormonal therapy with currently available antiandrogens and the leutinizing hormone releasing hormone (LHRH) analogs is not effective in the hormone-refractory stage of prostate cancer due to changes in androgen receptor (AR) signaling axis. In this refractory stage, AR continues to play a significant role in the growth of cancer cells even though the cancer cells are no longer dependent on the level of circulating androgens. METHODS. A series of 11β-Δ⁹-19 nortestosterone compounds were designed through structure-based rationale and tested for their binding affinity against AR and glucocorticoid receptor (GR) using fluorescence polarization assays, their agonistic ability to induce AR dependent transcription using PSA-driven report gene assays, and their growth inhibitory affects against a series of AR positive (LAPC4, LNCap, and CWR22R) and negative human prostate cancer cell lines (PC3) using MTT cell proliferation assays. RESULTS. This study proposes the design of novel bifunctional antiandrogens based on the conjugation of 11β and/or 7α-Δ⁹-19 nortestosterone class of steroidal compounds to the synthetic ligand for FK506-binding proteins. As a critical step towards the development of bifunctional antiandrogens, highly potent and AR-specific lead compounds were identified using in vitro data. The lead compounds identified in this study possessed low binding affinity for GR, indicating the absence of undesirable antiglucocorticoid activity. CONCLUSIONS. The results of this study validate our drug discovery rationale based on the structural biology of AR and pave the pay for future development of bifunctional compounds in order to block AR function in hormone refractory stage of prostate cancer.