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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...

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Autores principales: Messner, Elisabeth A., Steele, Thomas M., Tsamouri, Maria Malvina, Hejazi, Nazila, Gao, Allen C., Mudryj, Maria, Ghosh, Paramita M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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.
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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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