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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| Format: | Article |
| Language: | English |
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MDPI AG
2014-02-01
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| Series: | Biology |
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| Online Access: | http://www.mdpi.com/2079-7737/3/1/101 |
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| author | Jason Davenport Maurie Balch Lakshmi Galam Antwan Girgis Jessica Hall Brian S. J. Blagg Robert L. Matts |
| author_facet | Jason Davenport Maurie Balch Lakshmi Galam Antwan Girgis Jessica Hall Brian S. J. Blagg Robert L. Matts |
| author_sort | Jason Davenport |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-12T18:22:48Z |
| format | Article |
| id | doaj.art-1350f5985b8c413d9b00515bd4cba1f8 |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-12T18:22:48Z |
| publishDate | 2014-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-1350f5985b8c413d9b00515bd4cba1f82023-08-02T08:40:29ZengMDPI AGBiology2079-77372014-02-013110113810.3390/biology3010101biology3010101High-Throughput Screen of Natural Product Libraries for Hsp90 InhibitorsJason Davenport0Maurie Balch1Lakshmi Galam2Antwan Girgis3Jessica Hall4Brian S. J. Blagg5Robert L. Matts6Department of Biochemistry and Molecular Biology, 246 Noble Research Center, Oklahoma State University, Stillwater, OK 74078, USADepartment of Biochemistry and Molecular Biology, 246 Noble Research Center, Oklahoma State University, Stillwater, OK 74078, USADepartment of Biochemistry and Molecular Biology, 246 Noble Research Center, Oklahoma State University, Stillwater, OK 74078, USADepartment of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045, USADepartment of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045, USADepartment of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045, USADepartment of Biochemistry and Molecular Biology, 246 Noble Research Center, Oklahoma State University, Stillwater, OK 74078, USAHsp90 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.http://www.mdpi.com/2079-7737/3/1/101Hsp90Hsp90 inhibitorshigh-throughput screennatural products libraries |
| spellingShingle | Jason Davenport Maurie Balch Lakshmi Galam Antwan Girgis Jessica Hall Brian S. J. Blagg Robert L. Matts High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors Biology Hsp90 Hsp90 inhibitors high-throughput screen natural products libraries |
| 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 | Hsp90 Hsp90 inhibitors high-throughput screen natural products libraries |
| url | http://www.mdpi.com/2079-7737/3/1/101 |
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