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

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 pro...

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Bibliographic Details
Published in:	Science (American Association for the Advancement of Science) Vol. 356; no. 6342; p. 1084
Main Authors:	van Esbroeck, Annelot C M, Janssen, Antonius P A, Cognetta, 3rd, Armand B, Ogasawara, Daisuke, Shpak, Guy, van der Kroeg, Mark, Kantae, Vasudev, Baggelaar, Marc P, de Vrij, Femke M S, Deng, Hui, Allarà, Marco, Fezza, Filomena, Lin, Zhanmin, van der Wel, Tom, Soethoudt, Marjolein, Mock, Elliot D, den Dulk, Hans, Baak, Ilse L, Florea, Bogdan I, Hendriks, Giel, De Petrocellis, Luciano, Overkleeft, Herman S, Hankemeier, Thomas, De Zeeuw, Chris I, Di Marzo, Vincenzo, Maccarrone, Mauro, Cravatt, Benjamin F, Kushner, Steven A, van der Stelt, Mario
Format:	Journal Article
Language:	English
Published:	United States 09.06.2017
Subjects:	Amidohydrolases - antagonists & inhibitors Analgesics - adverse effects Analgesics - chemistry Analgesics - metabolism Analgesics - pharmacology Anti-Anxiety Agents - adverse effects Anti-Anxiety Agents - chemistry Anti-Anxiety Agents - metabolism Anti-Anxiety Agents - pharmacology Cell Line, Tumor Clinical Trials, Phase I as Topic Cross Reactions Cyclic N-Oxides - adverse effects Cyclic N-Oxides - chemistry Cyclic N-Oxides - metabolism Cyclic N-Oxides - pharmacology Humans Neurons - drug effects Neurons - metabolism Protein Interaction Maps Pyridazines - pharmacology Pyridazines - therapeutic use Pyridines - adverse effects Pyridines - chemistry Pyridines - metabolism Pyridines - pharmacology Urea - analogs & derivatives Urea - pharmacology Urea - therapeutic use
ISSN:	1095-9203, 1095-9203
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1095-9203 1095-9203
DOI:	10.1126/science.aaf7497