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Discovery and Identification of Pyrazolopyramidine Analogs as Novel Potent Androgen Receptor Antagonists
Androgen receptor (AR), an important target in the current androgen derivation therapy, plays a critical role in the development and progress of prostate cancer (PCa). Nonsteroidal antiandrogens, such as enzalutamide and bicalutamide, are commonly used in clinic to treat PCa. Though they are very ef...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121070/ https://www.ncbi.nlm.nih.gov/pubmed/30210333 http://dx.doi.org/10.3389/fphar.2018.00864 |
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author | Wang, Lingyan Song, Tianqing Wang, Xin Li, Jiazhong |
author_facet | Wang, Lingyan Song, Tianqing Wang, Xin Li, Jiazhong |
author_sort | Wang, Lingyan |
collection | PubMed |
description | Androgen receptor (AR), an important target in the current androgen derivation therapy, plays a critical role in the development and progress of prostate cancer (PCa). Nonsteroidal antiandrogens, such as enzalutamide and bicalutamide, are commonly used in clinic to treat PCa. Though they are very effective at the beginning, drug resistance problem appears after about 18 months. One of the reasons is that these antiandrogens share similar structure skeleton. Therefore, it is urgent to discover novel antiandrogens with different skeletons for resistance problem. Herein, we combined structure- and ligand-based methodologies for virtual screening chemical databases to identify potent AR antagonists. Then the cytotoxic activities of the screened hit samples were evaluated by using LNCaP prostate cancer cells. Virtual screening and biological evaluation assay results suggest that several chemicals with novel pyrazolopyrimidine skeleton can inhibit the proliferation of prostate cancer cells with similar, or even higher, bioactivities to bicalutamide. AR reporter gene assay experiments proved that Compound III showed potential antagonistic effects. In addition, molecular dynamics simulations results proved that Compound III can properly bind to AR and prevent helix 12 (H12) from closing to distort the formation of activation function 2 (AF2) site, resulting in the invalid transcription. Hence, pyrazolopyrimidine was discovered as a novel, potent and promising antiandrogen skeleton deserved to be further studied. |
format | Online Article Text |
id | pubmed-6121070 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61210702018-09-12 Discovery and Identification of Pyrazolopyramidine Analogs as Novel Potent Androgen Receptor Antagonists Wang, Lingyan Song, Tianqing Wang, Xin Li, Jiazhong Front Pharmacol Pharmacology Androgen receptor (AR), an important target in the current androgen derivation therapy, plays a critical role in the development and progress of prostate cancer (PCa). Nonsteroidal antiandrogens, such as enzalutamide and bicalutamide, are commonly used in clinic to treat PCa. Though they are very effective at the beginning, drug resistance problem appears after about 18 months. One of the reasons is that these antiandrogens share similar structure skeleton. Therefore, it is urgent to discover novel antiandrogens with different skeletons for resistance problem. Herein, we combined structure- and ligand-based methodologies for virtual screening chemical databases to identify potent AR antagonists. Then the cytotoxic activities of the screened hit samples were evaluated by using LNCaP prostate cancer cells. Virtual screening and biological evaluation assay results suggest that several chemicals with novel pyrazolopyrimidine skeleton can inhibit the proliferation of prostate cancer cells with similar, or even higher, bioactivities to bicalutamide. AR reporter gene assay experiments proved that Compound III showed potential antagonistic effects. In addition, molecular dynamics simulations results proved that Compound III can properly bind to AR and prevent helix 12 (H12) from closing to distort the formation of activation function 2 (AF2) site, resulting in the invalid transcription. Hence, pyrazolopyrimidine was discovered as a novel, potent and promising antiandrogen skeleton deserved to be further studied. Frontiers Media S.A. 2018-08-28 /pmc/articles/PMC6121070/ /pubmed/30210333 http://dx.doi.org/10.3389/fphar.2018.00864 Text en Copyright © 2018 Wang, Song, Wang and Li. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Wang, Lingyan Song, Tianqing Wang, Xin Li, Jiazhong Discovery and Identification of Pyrazolopyramidine Analogs as Novel Potent Androgen Receptor Antagonists |
title | Discovery and Identification of Pyrazolopyramidine Analogs as Novel Potent Androgen Receptor Antagonists |
title_full | Discovery and Identification of Pyrazolopyramidine Analogs as Novel Potent Androgen Receptor Antagonists |
title_fullStr | Discovery and Identification of Pyrazolopyramidine Analogs as Novel Potent Androgen Receptor Antagonists |
title_full_unstemmed | Discovery and Identification of Pyrazolopyramidine Analogs as Novel Potent Androgen Receptor Antagonists |
title_short | Discovery and Identification of Pyrazolopyramidine Analogs as Novel Potent Androgen Receptor Antagonists |
title_sort | discovery and identification of pyrazolopyramidine analogs as novel potent androgen receptor antagonists |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121070/ https://www.ncbi.nlm.nih.gov/pubmed/30210333 http://dx.doi.org/10.3389/fphar.2018.00864 |
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