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High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors

Hsp90 has become the target of intensive investigation, as inhibition of its function has the ability to simultaneously incapacitate proteins that function in pathways that represent the six hallmarks of cancer. While a number of Hsp90 inhibitors have made it into clinical trials, a number of short-...

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Autores principales: Davenport, Jason, Balch, Maurie, Galam, Lakshmi, Girgis, Antwan, Hall, Jessica, Blagg, Brian S. J., Matts, Robert L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009755/
https://www.ncbi.nlm.nih.gov/pubmed/24833337
http://dx.doi.org/10.3390/biology3010101
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author Davenport, Jason
Balch, Maurie
Galam, Lakshmi
Girgis, Antwan
Hall, Jessica
Blagg, Brian S. J.
Matts, Robert L.
author_facet Davenport, Jason
Balch, Maurie
Galam, Lakshmi
Girgis, Antwan
Hall, Jessica
Blagg, Brian S. J.
Matts, Robert L.
author_sort Davenport, Jason
collection PubMed
description Hsp90 has become the target of intensive investigation, as inhibition of its function has the ability to simultaneously incapacitate proteins that function in pathways that represent the six hallmarks of cancer. While a number of Hsp90 inhibitors have made it into clinical trials, a number of short-comings have been noted, such that the search continues for novel Hsp90 inhibitors with superior pharmacological properties. To identify new potential Hsp90 inhibitors, we have utilized a high-throughput assay based on measuring Hsp90-dependent refolding of thermally denatured luciferase to screen natural compound libraries. Over 4,000 compounds were screen with over 100 hits. Data mining of the literature indicated that 51 compounds had physiological effects that Hsp90 inhibitors also exhibit, and/or the ability to downregulate the expression levels of Hsp90-dependent proteins. Of these 51 compounds, seven were previously characterized as Hsp90 inhibitors. Four compounds, anthothecol, garcinol, piplartine, and rottlerin, were further characterized, and the ability of these compounds to inhibit the refolding of luciferase, and reduce the rate of growth of MCF7 breast cancer cells, correlated with their ability to suppress the Hsp90-dependent maturation of the heme-regulated eIF2α kinase, and deplete cultured cells of Hsp90-dependent client proteins. Thus, this screen has identified an additional 44 compounds with known beneficial pharmacological properties, but with unknown mechanisms of action as possible new inhibitors of the Hsp90 chaperone machine.
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spelling pubmed-40097552014-05-07 High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors Davenport, Jason Balch, Maurie Galam, Lakshmi Girgis, Antwan Hall, Jessica Blagg, Brian S. J. Matts, Robert L. Biology (Basel) Article Hsp90 has become the target of intensive investigation, as inhibition of its function has the ability to simultaneously incapacitate proteins that function in pathways that represent the six hallmarks of cancer. While a number of Hsp90 inhibitors have made it into clinical trials, a number of short-comings have been noted, such that the search continues for novel Hsp90 inhibitors with superior pharmacological properties. To identify new potential Hsp90 inhibitors, we have utilized a high-throughput assay based on measuring Hsp90-dependent refolding of thermally denatured luciferase to screen natural compound libraries. Over 4,000 compounds were screen with over 100 hits. Data mining of the literature indicated that 51 compounds had physiological effects that Hsp90 inhibitors also exhibit, and/or the ability to downregulate the expression levels of Hsp90-dependent proteins. Of these 51 compounds, seven were previously characterized as Hsp90 inhibitors. Four compounds, anthothecol, garcinol, piplartine, and rottlerin, were further characterized, and the ability of these compounds to inhibit the refolding of luciferase, and reduce the rate of growth of MCF7 breast cancer cells, correlated with their ability to suppress the Hsp90-dependent maturation of the heme-regulated eIF2α kinase, and deplete cultured cells of Hsp90-dependent client proteins. Thus, this screen has identified an additional 44 compounds with known beneficial pharmacological properties, but with unknown mechanisms of action as possible new inhibitors of the Hsp90 chaperone machine. MDPI 2014-02-10 /pmc/articles/PMC4009755/ /pubmed/24833337 http://dx.doi.org/10.3390/biology3010101 Text en © 2014 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 license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Davenport, Jason
Balch, Maurie
Galam, Lakshmi
Girgis, Antwan
Hall, Jessica
Blagg, Brian S. J.
Matts, Robert L.
High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors
title High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors
title_full High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors
title_fullStr High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors
title_full_unstemmed High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors
title_short High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors
title_sort high-throughput screen of natural product libraries for hsp90 inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009755/
https://www.ncbi.nlm.nih.gov/pubmed/24833337
http://dx.doi.org/10.3390/biology3010101
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