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

Author

van Esbroeck, ACM, Janssen, APA, Cognetta, AB, Ogasawara, D, Shpak, Guy, Kroeg, Mark, Kantae, V, Baggelaar, MP, de Vrij, Femke, Deng, H, Allara, M, Fezza, F, Lin, Zhanmin, Wel, Twan, Soethoudt, M, Mock, ED, den Dulk, H, Baak, IL, Florea, BI, Hendriks, G, de Petrocellis, L, Overkleeft, HS, Hankemeier, T, de Zeeuw, Chris, Di Marzo, V, Maccarrone, M, Cravatt, BF, Kushner, Steven, van der Stelt, M, van Esbroeck, ACM, Janssen, APA, Cognetta, AB, Ogasawara, D, Shpak, Guy, Kroeg, Mark, Kantae, V, Baggelaar, MP, de Vrij, Femke, Deng, H, Allara, M, Fezza, F, Lin, Zhanmin, Wel, Twan, Soethoudt, M, Mock, ED, den Dulk, H, Baak, IL, Florea, BI, Hendriks, G, de Petrocellis, L, Overkleeft, HS, Hankemeier, T, de Zeeuw, Chris, Di Marzo, V, Maccarrone, M, Cravatt, BF, Kushner, Steven, and van der Stelt, M

Published
2017

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

Author

van Esbroeck ACM, Janssen APA, Cognetta AB 3rd, Ogasawara D, Shpak G, van der Kroeg M, Kantae V, Baggelaar MP, de Vrij FMS, Deng H, Allarà M, Fezza F, Lin Z, van der Wel T, Soethoudt M, Mock ED, den Dulk H, Baak IL, Florea BI, Hendriks G, De Petrocellis L, Overkleeft HS, Hankemeier T, De Zeeuw CI, Di Marzo V, Maccarrone M, Cravatt BF, Kushner SA, and van der Stelt M

Subjects
Analgesics adverse effects, Analgesics chemistry, Analgesics metabolism, Anti-Anxiety Agents adverse effects, Anti-Anxiety Agents chemistry, Anti-Anxiety Agents metabolism, Cell Line, Tumor, Clinical Trials, Phase I as Topic, Cross Reactions, Cyclic N-Oxides adverse effects, Cyclic N-Oxides chemistry, Cyclic N-Oxides metabolism, Humans, Neurons metabolism, Protein Interaction Maps, Pyridazines pharmacology, Pyridazines therapeutic use, Pyridines adverse effects, Pyridines chemistry, Pyridines metabolism, Urea analogs & derivatives, Urea pharmacology, Urea therapeutic use, Amidohydrolases antagonists & inhibitors, Analgesics pharmacology, Anti-Anxiety Agents pharmacology, Cyclic N-Oxides pharmacology, Neurons drug effects, Pyridines pharmacology
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 proteomic methods 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., (Copyright © 2017, American Association for the Advancement of Science.)

Published
2017
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