Androgen receptor antagonists for prostate cancer therapy

  1. Frank Claessens1
  1. 1Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium
    2Urology, Department of Development and Regeneration, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
    3Laboratory for Structural Bioinformatics, Center for Life Science Technologies, RIKEN, Yokohama, Japan
  1. Correspondence should be addressed to F Claessens; Email: frank.claessens{at}
  1. Figure 1

    Overview of prostate cancer therapy. This scheme gives the therapeutic options assigned to each stage of prostate cancer disease. Based on tumor characteristics, patients' health status, biological age, and personal preference, the optimal therapeutic regimen can be chosen. Treatments with a dotted frame are not considered as standard therapy according to the EAU guidelines. HT, hormone therapy; NSAA, non-steroidal antiandrogen. Adapted from Higano & Crawford (2011) and Massard & Fizazi (2011).

  2. Figure 2

    Androgen deprivation therapy. Depriving the tumor from androgens is one strategy to tackle uncontrolled androgen signaling by the AR. LHRH analogues, both agonists and antagonists, are able to inhibit the synthesis of testosterone in the testis and of DHEA in the adrenal glands by affecting the hypothalamic–pituitary–gonadal/adrenal axis. CYP17A1 inhibitors cause androgen deprivation by inhibiting the intracellular biosynthesis of androgens in the testis and adrenals starting from cholesterol. Besides reduced testosterone, DHT, and DHEA levels, some CYP17A1 inhibitors (e.g., abiraterone and TOK-001) are also able to directly bind to the androgen receptor (AR) and block its activity as a ligand-dependent transcription factor. LHRH, luteinizing hormone-releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; ACTH, adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; AF1, activation function 1; CoR, corepressor complexes.

  3. Figure 3

    Steroidal antiandrogens and CYP17 inhibitors. The CYP17 inhibitors with a steroidal structure also display antiandrogenic effects by binding directly to the AR. DHT, dihydrotestosterone; CPA, cyproterone acetate; MPA, medroxyprogesterone acetate.

  4. Figure 4

    Mechanism of action of AR antagonists. After binding to the ligand-binding pocket of AR and nuclear translocation of AR, dihydrotestosterone (DHT) is able to induce the formation of a coactivator-binding platform, called AF1, which leads to the recruitment of coactivators (CoA). These coactivators will induce the formation of an active transcriptional complex containing RNA polymerase that leads to transcription of androgen-regulated genes. AR antagonists can interfere with all of these required events for activation of AR gene expression by an androgen. Bicalutamide (bic) binds to the ligand-binding pocket of AR but fails to induce the correct conformational change. The platform that is formed cannot recruit coactivators, but corepressors (CoR) leading to an inactive AR–DNA complex. Enzalutamide (Enz) has a similar mechanism of action as bic, but can prevent nuclear translocation of the AR and the binding of AR to DNA as well, making it a stronger AR antagonist.

  5. Figure 5

    Non-steroidal antiandrogens. Both the first- and second-generation antiandrogens that are currently being used in clinical practice share a structural motif consisting of an anilide substituted with a trifluoromethyl group in meta-position and a nitro- or cyano-group in para-position. In nilutamide, enzalutamide, and ARN-509, the amide of the anilide is a part of (thio)hydantoin.

  6. Figure 6

    Similar binding modes of bic and enz to the AR ligand-binding pocket. In silico model of bic (A) and enz (B) binding as an antagonist in the ligand-binding domain of the human AR according to Voet et al. (2013). Both molecules show key conserved interactions in the deeper end of the pocket where the common trifluoromethyl cyano benzyl group is accommodated in a highly hydrophobic area with the exception of one hydrogen bridge with arginine 752 (R752).

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