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

Abstract

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.

Probing the Topological Tolerance of Multimeric Protein Interactions: Evaluation of an Estrogen/Synthetic Ligand for FK506 Binding Protein Conjugate

“…Another option in designing estrogen-SLF conjugates would be to supplement the activity of an antiestrogen by appending an SLF moiety; in fact, such a design has been reported for the androgen receptor (34). We have attempted to create such compounds for the estrogen receptor, but we have had difficulty in synthesizing one that has sufficient ER affinity to be examined in our assays.…”

Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target

“…Compounds have been synthesized with higher affinity for AR than bicalutamide, and that more potently antagonize transcriptional activation via the W741C and T877A mutant ARs (26, 41-44). Another strategy has been to incorporate steric hindrance by linking a potent AR agonist to a ligand of the ubiquitous FK506-binding proteins (FKBPs) (45). A third strategy has utilized a fluorescence based screen to identify compounds that inhibit AR nuclear translocation and the interaction between the N- and C-terminus (46).…”

New Approaches Targeting Androgen Receptor Signal Pathways for Treatment of Castration-Resistant Prostate Cancer

“…The failure of hormonal therapy for prostate cancer has been largely attributed to overexpression of AR in recurrence of the cancer (Chi et al, 2009;Joseph et al, 2009;Norris et al, 2009;Singh et al, 2008;Tran et al, 2009;Zhou et al, 2008). Development of more effective hormonal therapeutic agents targeting overexpressed AR becomes an important research area.…”

“…Many AR antagonists previously developed are mainly ligand competitors for androgens and can not overcome the over-expressed AR in CRPC. Newer approaches have been used to develop agents that can target potential sites in the AR to abrogate the function of the mutated or over-expressed receptor in cancer cells (Chi et al, 2009;Joseph et al, 2009;Norris et al, 2009;Singh et al, 2008;Tran et al, 2009;Zhou et al, 2008;Shen & Balk, 2009). For example, it was reported that a conformation-based assay was used to screen a diverse small molecule library of ≈10,000 compounds in order to select chemicals that can inhibit the AR-gelsolin interaction .…”