A High-Content Assay Enables the Automated Screening and Identification of Small Molecules with Specific ALDH1A1-Inhibitory Activity.
Aldehyde dehydrogenase enzymes (ALDHs) have a broad spectrum of biological activities through the oxidation of both endogenous and exogenous aldehydes. Increased expression of ALDH1A1 has been identified in a wide-range of human cancer stem cells and is associated with cancer relapse and poor progno...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5271370?pdf=render |
| _version_ | 1818048761445744640 |
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| author | Adam Yasgar Steven A Titus Yuhong Wang Carina Danchik Shyh-Ming Yang Vasilis Vasiliou Ajit Jadhav David J Maloney Anton Simeonov Natalia J Martinez |
| author_facet | Adam Yasgar Steven A Titus Yuhong Wang Carina Danchik Shyh-Ming Yang Vasilis Vasiliou Ajit Jadhav David J Maloney Anton Simeonov Natalia J Martinez |
| author_sort | Adam Yasgar |
| collection | DOAJ |
| description | Aldehyde dehydrogenase enzymes (ALDHs) have a broad spectrum of biological activities through the oxidation of both endogenous and exogenous aldehydes. Increased expression of ALDH1A1 has been identified in a wide-range of human cancer stem cells and is associated with cancer relapse and poor prognosis, raising the potential of ALDH1A1 as a therapeutic target. To facilitate quantitative high-throughput screening (qHTS) campaigns for the discovery, characterization and structure-activity-relationship (SAR) studies of small molecule ALDH1A1 inhibitors with cellular activity, we show herein the miniaturization to 1536-well format and automation of a high-content cell-based ALDEFLUOR assay. We demonstrate the utility of this assay by generating dose-response curves on a comprehensive set of prior art inhibitors as well as hundreds of ALDH1A1 inhibitors synthesized in house. Finally, we established a screening paradigm using a pair of cell lines with low and high ALDH1A1 expression, respectively, to uncover novel cell-active ALDH1A1-specific inhibitors from a collection of over 1,000 small molecules. |
| first_indexed | 2024-12-10T10:26:49Z |
| format | Article |
| id | doaj.art-92a0cb939abb4cf0b33cbcec4974a58a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T10:26:49Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-92a0cb939abb4cf0b33cbcec4974a58a2022-12-22T01:52:41ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01121e017093710.1371/journal.pone.0170937A High-Content Assay Enables the Automated Screening and Identification of Small Molecules with Specific ALDH1A1-Inhibitory Activity.Adam YasgarSteven A TitusYuhong WangCarina DanchikShyh-Ming YangVasilis VasiliouAjit JadhavDavid J MaloneyAnton SimeonovNatalia J MartinezAldehyde dehydrogenase enzymes (ALDHs) have a broad spectrum of biological activities through the oxidation of both endogenous and exogenous aldehydes. Increased expression of ALDH1A1 has been identified in a wide-range of human cancer stem cells and is associated with cancer relapse and poor prognosis, raising the potential of ALDH1A1 as a therapeutic target. To facilitate quantitative high-throughput screening (qHTS) campaigns for the discovery, characterization and structure-activity-relationship (SAR) studies of small molecule ALDH1A1 inhibitors with cellular activity, we show herein the miniaturization to 1536-well format and automation of a high-content cell-based ALDEFLUOR assay. We demonstrate the utility of this assay by generating dose-response curves on a comprehensive set of prior art inhibitors as well as hundreds of ALDH1A1 inhibitors synthesized in house. Finally, we established a screening paradigm using a pair of cell lines with low and high ALDH1A1 expression, respectively, to uncover novel cell-active ALDH1A1-specific inhibitors from a collection of over 1,000 small molecules.http://europepmc.org/articles/PMC5271370?pdf=render |
| spellingShingle | Adam Yasgar Steven A Titus Yuhong Wang Carina Danchik Shyh-Ming Yang Vasilis Vasiliou Ajit Jadhav David J Maloney Anton Simeonov Natalia J Martinez A High-Content Assay Enables the Automated Screening and Identification of Small Molecules with Specific ALDH1A1-Inhibitory Activity. PLoS ONE |
| title | A High-Content Assay Enables the Automated Screening and Identification of Small Molecules with Specific ALDH1A1-Inhibitory Activity. |
| title_full | A High-Content Assay Enables the Automated Screening and Identification of Small Molecules with Specific ALDH1A1-Inhibitory Activity. |
| title_fullStr | A High-Content Assay Enables the Automated Screening and Identification of Small Molecules with Specific ALDH1A1-Inhibitory Activity. |
| title_full_unstemmed | A High-Content Assay Enables the Automated Screening and Identification of Small Molecules with Specific ALDH1A1-Inhibitory Activity. |
| title_short | A High-Content Assay Enables the Automated Screening and Identification of Small Molecules with Specific ALDH1A1-Inhibitory Activity. |
| title_sort | high content assay enables the automated screening and identification of small molecules with specific aldh1a1 inhibitory activity |
| url | http://europepmc.org/articles/PMC5271370?pdf=render |
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