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The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy
The androgen receptor (AR) plays a predominant role in prostate cancer (PCa) pathology. It consists of an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region (HR), and a ligand-binding domain (LBD) that binds androgens, including testosterone (T) and dihydrotestosterone (DHT). Ligand...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602609/ https://www.ncbi.nlm.nih.gov/pubmed/33076388 http://dx.doi.org/10.3390/biomedicines8100422 |
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author | Messner, Elisabeth A. Steele, Thomas M. Tsamouri, Maria Malvina Hejazi, Nazila Gao, Allen C. Mudryj, Maria Ghosh, Paramita M. |
author_facet | Messner, Elisabeth A. Steele, Thomas M. Tsamouri, Maria Malvina Hejazi, Nazila Gao, Allen C. Mudryj, Maria Ghosh, Paramita M. |
author_sort | Messner, Elisabeth A. |
collection | PubMed |
description | The androgen receptor (AR) plays a predominant role in prostate cancer (PCa) pathology. It consists of an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region (HR), and a ligand-binding domain (LBD) that binds androgens, including testosterone (T) and dihydrotestosterone (DHT). Ligand binding at the LBD promotes AR dimerization and translocation to the nucleus where the DBD binds target DNA. In PCa, AR signaling is perturbed by excessive androgen synthesis, AR amplification, mutation, or the formation of AR alternatively spliced variants (AR-V) that lack the LBD. Current therapies for advanced PCa include androgen synthesis inhibitors that suppress T and/or DHT synthesis, and AR inhibitors that prevent ligand binding at the LBD. However, AR mutations and AR-Vs render LBD-specific therapeutics ineffective. The DBD and NTD are novel targets for inhibition as both perform necessary roles in AR transcriptional activity and are less susceptible to AR alternative splicing compared to the LBD. DBD and NTD inhibition can potentially extend patient survival, improve quality of life, and overcome predominant mechanisms of resistance to current therapies. This review discusses various small molecule and other inhibitors developed against the DBD and NTD—and the current state of the available compounds in clinical development. |
format | Online Article Text |
id | pubmed-7602609 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76026092020-11-01 The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy Messner, Elisabeth A. Steele, Thomas M. Tsamouri, Maria Malvina Hejazi, Nazila Gao, Allen C. Mudryj, Maria Ghosh, Paramita M. Biomedicines Review The androgen receptor (AR) plays a predominant role in prostate cancer (PCa) pathology. It consists of an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region (HR), and a ligand-binding domain (LBD) that binds androgens, including testosterone (T) and dihydrotestosterone (DHT). Ligand binding at the LBD promotes AR dimerization and translocation to the nucleus where the DBD binds target DNA. In PCa, AR signaling is perturbed by excessive androgen synthesis, AR amplification, mutation, or the formation of AR alternatively spliced variants (AR-V) that lack the LBD. Current therapies for advanced PCa include androgen synthesis inhibitors that suppress T and/or DHT synthesis, and AR inhibitors that prevent ligand binding at the LBD. However, AR mutations and AR-Vs render LBD-specific therapeutics ineffective. The DBD and NTD are novel targets for inhibition as both perform necessary roles in AR transcriptional activity and are less susceptible to AR alternative splicing compared to the LBD. DBD and NTD inhibition can potentially extend patient survival, improve quality of life, and overcome predominant mechanisms of resistance to current therapies. This review discusses various small molecule and other inhibitors developed against the DBD and NTD—and the current state of the available compounds in clinical development. MDPI 2020-10-15 /pmc/articles/PMC7602609/ /pubmed/33076388 http://dx.doi.org/10.3390/biomedicines8100422 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Messner, Elisabeth A. Steele, Thomas M. Tsamouri, Maria Malvina Hejazi, Nazila Gao, Allen C. Mudryj, Maria Ghosh, Paramita M. The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy |
title | The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy |
title_full | The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy |
title_fullStr | The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy |
title_full_unstemmed | The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy |
title_short | The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy |
title_sort | androgen receptor in prostate cancer: effect of structure, ligands and spliced variants on therapy |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602609/ https://www.ncbi.nlm.nih.gov/pubmed/33076388 http://dx.doi.org/10.3390/biomedicines8100422 |
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