A sting in the tail: the N-terminal domain of the androgen receptor as a drug target
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 of...
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doaj-f712fed545034160a14ba893e466f7a32020-11-24T22:32:49ZengWolters Kluwer Medknow PublicationsAsian Journal of Andrology1008-682X1745-72622016-01-0118568769410.4103/1008-682X.181081A sting in the tail: the N-terminal domain of the androgen receptor as a drug targetAmy E MonaghanIain J McEwanThe 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-001 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.http://www.ajandrology.com/article.asp?issn=1008-682X;year=2016;volume=18;issue=5;spage=687;epage=694;aulast=Monaghanandrogen receptor; inhibitor; intrinsically disordered structure; N-terminal domain; prostate cancer; small molecules |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Amy E Monaghan Iain J McEwan |
spellingShingle |
Amy E Monaghan Iain J McEwan A sting in the tail: the N-terminal domain of the androgen receptor as a drug target Asian Journal of Andrology androgen receptor; inhibitor; intrinsically disordered structure; N-terminal domain; prostate cancer; small molecules |
author_facet |
Amy E Monaghan Iain J McEwan |
author_sort |
Amy E Monaghan |
title |
A sting in the tail: the N-terminal domain of the androgen receptor as a drug target |
title_short |
A sting in the tail: the N-terminal domain of the androgen receptor as a drug target |
title_full |
A sting in the tail: the N-terminal domain of the androgen receptor as a drug target |
title_fullStr |
A sting in the tail: the N-terminal domain of the androgen receptor as a drug target |
title_full_unstemmed |
A sting in the tail: the N-terminal domain of the androgen receptor as a drug target |
title_sort |
sting in the tail: the n-terminal domain of the androgen receptor as a drug target |
publisher |
Wolters Kluwer Medknow Publications |
series |
Asian Journal of Andrology |
issn |
1008-682X 1745-7262 |
publishDate |
2016-01-01 |
description |
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-001 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. |
topic |
androgen receptor; inhibitor; intrinsically disordered structure; N-terminal domain; prostate cancer; small molecules |
url |
http://www.ajandrology.com/article.asp?issn=1008-682X;year=2016;volume=18;issue=5;spage=687;epage=694;aulast=Monaghan |
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