Molecules targeting the androgen receptor (AR) signaling axis beyond the AR‐Ligand binding domain

• Published in: Medicinal research reviews 2019-05, Vol.39 (3), p.910-960
• Main Authors: Elshan, N. G. R. Dayan, Rettig, Matthew B., Jung, Michael E.
• Format: Article
• Language: English
• Subjects: androgen receptor; androgen receptor degradation; androgen receptor DNA‐binding domain; androgen receptor signaling axis; androgen receptor transactivation domain; Androgens; Animals; Binding sites; castration‐resistant prostate cancer; Clinical Trials as Topic; Disease Progression; Humans; Ligands; Prostate cancer; Protein Domains; Receptors, Androgen - chemistry; Receptors, Androgen - metabolism; Signal Transduction; Transcription factors
• ISSN: 0198-6325; 1098-1128; 1098-1128
• DOI: 10.1002/med.21548

Prostate cancer (PCa) is the second most common cause of cancer‐related mortality in men in the United States. The androgen receptor (AR) and the physiological pathways it regulates are central to the initiation and progression of PCa. As a member of the nuclear steroid receptor family, it is a transcription factor with three distinct functional domains (ligand‐binding domain [LBD], DNA‐binding domain [DBD], and transactivation domain [TAD]) in its structure. All clinically approved drugs for PCa ultimately target the AR‐LBD. Clinically active drugs that target the DBD and TAD have not yet been developed due to multiple factors. Despite these limitations, the last several years have seen a rise in the discovery of molecules that could successfully target these domains. This review aims to present and comprehensively discuss such molecules that affect AR signaling through direct or indirect interactions with the AR‐TAD or the DBD. The compounds discussed here include hairpin polyamides, niclosamide, marine sponge–derived small molecules (eg, EPI compounds), mahanine, VPC compounds, JN compounds, and bromodomain and extraterminal domain inhibitors. We highlight the significant in vitro and in vivo data found for each compound and the apparent limitations and/or potential for further development of these agents as PCa therapies.