A sting in the tail： the N-terminal domain of the androgen receptor as a drug target

• Published in: Asian journal of andrology Vol. 18; no. 5; pp. 687 - 694
• Main Authors: Monaghan, Amy, McEwan, Iain
• Format: Journal Article
• Language: English
• Published: China Wolters Kluwer - Medknow Publications 01.09.2016; Medknow Publications and Media Pvt. Ltd; Medknow Publications & Media Pvt. Ltd; Medknow Publications & Media Pvt Ltd; Wolters Kluwer Medknow Publications
• Subjects: Amino acids; Androgen Receptor Antagonists - therapeutic use; androgen receptor; inhibitor; intrinsically disordered structure; N-terminal domain; prostate cancer; small molecules; Androgen suppression therapy; Androgens; Care and treatment; Deoxyribonucleic acid; Disease Progression; DNA; DNA methylation; Gene expression; Humans; Invited Review; Ligands; Localization; Male; Methods; Mutation; N-末端; Patients; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Receptors, Androgen - metabolism; Transcription factors; Transcriptional Activation; 前列腺癌; 激素疗法; 结构域; 药物; 蛋白质-蛋白质相互作用; 雄激素受体; 靶向治疗
• ISSN: 1008-682X; 1745-7262
• DOI: 10.4103/1008-682X.181081

The role of androgen receptor （AR） in the initiation and progression of prostate cancer （PCa） is well established. Competitive inhibition of the AR ligand-binding domain （LBD） has been the staple of antiandrogen therapies employed to combat the disease in recent years. However, their efficacy has often been limited by the emergence of resistance, mediated through point mutations, and receptor truncations. As a result, the prognosis for patients with malignant castrate resistant disease remains poor. The amino-terminal domain （NTD） of the AR has been shown to be critical for AR function. Its modular activation function （AF-1） is important for both gene regulation and participation in protein-protein interactions. However, due to the intrinsically disordered structure of the domain, its potential as a candidate for therapeutic intervention has been dismissed in the past. The recent emergence of the small molecule EPI-O01 has provided evidence that AR-NTD can be targeted therapeutically, independent of the LBD. Targeting of AR-NTD has the potential to disrupt multiple intermolecular interactions between AR and its coregulatory binding partners, in addition to intramolecular cross-talk between the domains of the AR. Therapeutics targeting these protein-protein interactions or NTD directly should also have efficacy against emerging AR splice variants which may play a role in PCa progression. This review will discuss the role of intrinsic disorder in AR function and illustrate how emerging therapies might target NTD in PCa.