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The role of the AR in the development and progression of prostate cancer has led to increasing interest in this nuclear receptor. A complete loss of AR function in males results in complete androgen insensitivity syndrome 13, 14. Male sexual differentiation fails to occur in the absence of androgens or without a functioning AR. In the nucleus, receptor dimers bind to androgen response elements (AREs) in the promoter regions of target genes, such as prostate-specific antigen (PSA) and transmembrane protease serine 2 (TMPRSS2), etc, to which they recruit various coregulatory proteins to facilitate transcription, leading to responses such as growth and survival 7, 8, 9, 10, 11, 12. DHT binds to the AR with high affinity, displaces heat-shock proteins from the AR, drives the interaction between the N and C termini of the AR, and binds importin-О± to translocate the AR into the nucleus 6.

Intracellularly, testosterone is converted into a more potent 5О±-reduced metabolite of testosterone, 5О±-dihydrotestosterone (DHT), which promotes the growth and survival of prostate cells.

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Only the free form enters prostate cells. Once produced, testosterone mostly circulates bound to serum sex hormone-binding globulin (SHBG) and albumin 4, 5. LH secretion is in turn regulated by gonadotropin-releasing hormone (GnRH). Androgens such as testosterone are synthesized primarily by the Leydig cells in the testes, under the regulation of luteinizing hormone (LH) produced by the anterior pituitary gland. The current model of action of androgens and the AR is depicted in Figure 1A. The binding of the AR to its native ligands 5О±-dihydrotestosterone (DHT) and testosterone initiates male sexual development and differentiation. The AR is a ligand-dependent transcription factor that controls the expression of specific genes. The androgen receptor (AR) (NR3C4, nuclear receptor subfamily 3, group C, gene 4) belongs to the steroid hormone group of nuclear receptors with the estrogen receptor (ER), glucocorticoid receptor (GR), progesterone receptor (PR) and mineralocorticoid receptor (MR) 1, 2, 3. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. Early studies focused on the functional domains of the AR and its crucial role in the pathology. In CRPC, a functional AR remains a key regulator. However, resistance to these drugs often occurs after 2вЂ“3 years as the patients develop castration-resistant prostate cancer (CRPC).

Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype.

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