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Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474.

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Title: Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474.
Authors: van Esbroeck, Annelot C. M., Janssen, Antonius P. A., Cognetta III, Armand B., Ogasawara, Daisuke, Shpak, Guy, van der Kroeg, Mark, Kantae, Vasudev, Baggelaar, Marc P., de Vrij, Femke M. S., Hui Deng, Allarà, Marco, Fezza, Filomena, Zhanmin Lin, van der Wel, Tom, Soethoudt, Marjolein, Mock, Elliot D., den Dulk, Hans, Baak, Ilse L., Florea, Bogdan I., Hendriks, Giel
Source: Science (pre-March 2025). 6/9/2017, Vol. 356 Issue 6342, p1084-1087. 4p. 1 Color Photograph, 1 Chart, 2 Graphs.
Subjects: Proteomics, Protein-protein interactions, Lipases, Fatty acids, Lipase inhibitors
Abstract: A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomicmethods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system. [ABSTRACT FROM AUTHOR]
Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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PubTypeId: academicJournal
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  Data: Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474.
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  Data: <searchLink fieldCode="AR" term="%22van+Esbroeck%2C+Annelot+C%2E+M%2E%22">van Esbroeck, Annelot C. M.</searchLink><br /><searchLink fieldCode="AR" term="%22Janssen%2C+Antonius+P%2E+A%2E%22">Janssen, Antonius P. A.</searchLink><br /><searchLink fieldCode="AR" term="%22Cognetta+III%2C+Armand+B%2E%22">Cognetta III, Armand B.</searchLink><br /><searchLink fieldCode="AR" term="%22Ogasawara%2C+Daisuke%22">Ogasawara, Daisuke</searchLink><br /><searchLink fieldCode="AR" term="%22Shpak%2C+Guy%22">Shpak, Guy</searchLink><br /><searchLink fieldCode="AR" term="%22van+der+Kroeg%2C+Mark%22">van der Kroeg, Mark</searchLink><br /><searchLink fieldCode="AR" term="%22Kantae%2C+Vasudev%22">Kantae, Vasudev</searchLink><br /><searchLink fieldCode="AR" term="%22Baggelaar%2C+Marc+P%2E%22">Baggelaar, Marc P.</searchLink><br /><searchLink fieldCode="AR" term="%22de+Vrij%2C+Femke+M%2E+S%2E%22">de Vrij, Femke M. S.</searchLink><br /><searchLink fieldCode="AR" term="%22Hui+Deng%22">Hui Deng</searchLink><br /><searchLink fieldCode="AR" term="%22Allarà%2C+Marco%22">Allarà, Marco</searchLink><br /><searchLink fieldCode="AR" term="%22Fezza%2C+Filomena%22">Fezza, Filomena</searchLink><br /><searchLink fieldCode="AR" term="%22Zhanmin+Lin%22">Zhanmin Lin</searchLink><br /><searchLink fieldCode="AR" term="%22van+der+Wel%2C+Tom%22">van der Wel, Tom</searchLink><br /><searchLink fieldCode="AR" term="%22Soethoudt%2C+Marjolein%22">Soethoudt, Marjolein</searchLink><br /><searchLink fieldCode="AR" term="%22Mock%2C+Elliot+D%2E%22">Mock, Elliot D.</searchLink><br /><searchLink fieldCode="AR" term="%22den+Dulk%2C+Hans%22">den Dulk, Hans</searchLink><br /><searchLink fieldCode="AR" term="%22Baak%2C+Ilse+L%2E%22">Baak, Ilse L.</searchLink><br /><searchLink fieldCode="AR" term="%22Florea%2C+Bogdan+I%2E%22">Florea, Bogdan I.</searchLink><br /><searchLink fieldCode="AR" term="%22Hendriks%2C+Giel%22">Hendriks, Giel</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Science+%28pre-March+2025%29%22">Science (pre-March 2025)</searchLink>. 6/9/2017, Vol. 356 Issue 6342, p1084-1087. 4p. 1 Color Photograph, 1 Chart, 2 Graphs.
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  Data: <searchLink fieldCode="DE" term="%22Proteomics%22">Proteomics</searchLink><br /><searchLink fieldCode="DE" term="%22Protein-protein+interactions%22">Protein-protein interactions</searchLink><br /><searchLink fieldCode="DE" term="%22Lipases%22">Lipases</searchLink><br /><searchLink fieldCode="DE" term="%22Fatty+acids%22">Fatty acids</searchLink><br /><searchLink fieldCode="DE" term="%22Lipase+inhibitors%22">Lipase inhibitors</searchLink>
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  Label: Abstract
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  Data: A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomicmethods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=123545465
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        Value: 10.1126/science.aaf7497
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        Text: English
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