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. |
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| 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] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| 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] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.aaf7497 |
