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Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance

The androgen receptor is a major driver of prostate cancer and inhibition of its transcriptional activity using competitive antagonists, such as enzalutamide remains a frontline therapy for prostate cancer management. However, the majority of patients eventually develop drug resistance. We propose t...

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Autores principales: Salami, Jemilat, Alabi, Shanique, Willard, Ryan R., Vitale, Nick J., Wang, Jing, Dong, Hanqing, Jin, Meizhong, McDonnell, Donald P., Crew, Andrew P., Neklesa, Taavi K., Crews, Craig M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123676/
https://www.ncbi.nlm.nih.gov/pubmed/30271980
http://dx.doi.org/10.1038/s42003-018-0105-8
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author Salami, Jemilat
Alabi, Shanique
Willard, Ryan R.
Vitale, Nick J.
Wang, Jing
Dong, Hanqing
Jin, Meizhong
McDonnell, Donald P.
Crew, Andrew P.
Neklesa, Taavi K.
Crews, Craig M.
author_facet Salami, Jemilat
Alabi, Shanique
Willard, Ryan R.
Vitale, Nick J.
Wang, Jing
Dong, Hanqing
Jin, Meizhong
McDonnell, Donald P.
Crew, Andrew P.
Neklesa, Taavi K.
Crews, Craig M.
author_sort Salami, Jemilat
collection PubMed
description The androgen receptor is a major driver of prostate cancer and inhibition of its transcriptional activity using competitive antagonists, such as enzalutamide remains a frontline therapy for prostate cancer management. However, the majority of patients eventually develop drug resistance. We propose that targeting the androgen receptor for degradation via Proteolysis Targeting Chimeras (PROTACs) will be a better therapeutic strategy for targeting androgen receptor signaling in prostate cancer cells. Here we perform a head-to-head comparison between a currently approved androgen receptor antagonist enzalutamide, and its PROTAC derivative, ARCC-4, across different cellular models of prostate cancer drug resistance. ARCC-4 is a low-nanomolar androgen receptor degrader able to degrade about 95% of cellular androgen receptors. ARCC-4 inhibits prostate tumor cell proliferation, degrades clinically relevant androgen receptor point mutants and unlike enzalutamide, retains antiproliferative effect in a high androgen environment. Thus, ARCC-4 exemplifies how protein degradation can address the drug resistance hurdles of enzalutamide.
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spelling pubmed-61236762018-09-28 Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance Salami, Jemilat Alabi, Shanique Willard, Ryan R. Vitale, Nick J. Wang, Jing Dong, Hanqing Jin, Meizhong McDonnell, Donald P. Crew, Andrew P. Neklesa, Taavi K. Crews, Craig M. Commun Biol Article The androgen receptor is a major driver of prostate cancer and inhibition of its transcriptional activity using competitive antagonists, such as enzalutamide remains a frontline therapy for prostate cancer management. However, the majority of patients eventually develop drug resistance. We propose that targeting the androgen receptor for degradation via Proteolysis Targeting Chimeras (PROTACs) will be a better therapeutic strategy for targeting androgen receptor signaling in prostate cancer cells. Here we perform a head-to-head comparison between a currently approved androgen receptor antagonist enzalutamide, and its PROTAC derivative, ARCC-4, across different cellular models of prostate cancer drug resistance. ARCC-4 is a low-nanomolar androgen receptor degrader able to degrade about 95% of cellular androgen receptors. ARCC-4 inhibits prostate tumor cell proliferation, degrades clinically relevant androgen receptor point mutants and unlike enzalutamide, retains antiproliferative effect in a high androgen environment. Thus, ARCC-4 exemplifies how protein degradation can address the drug resistance hurdles of enzalutamide. Nature Publishing Group UK 2018-08-02 /pmc/articles/PMC6123676/ /pubmed/30271980 http://dx.doi.org/10.1038/s42003-018-0105-8 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Salami, Jemilat
Alabi, Shanique
Willard, Ryan R.
Vitale, Nick J.
Wang, Jing
Dong, Hanqing
Jin, Meizhong
McDonnell, Donald P.
Crew, Andrew P.
Neklesa, Taavi K.
Crews, Craig M.
Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance
title Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance
title_full Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance
title_fullStr Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance
title_full_unstemmed Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance
title_short Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance
title_sort androgen receptor degradation by the proteolysis-targeting chimera arcc-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123676/
https://www.ncbi.nlm.nih.gov/pubmed/30271980
http://dx.doi.org/10.1038/s42003-018-0105-8
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