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

• Published in: Science (American Association for the Advancement of Science) Vol. 356; no. 6342; pp. 1084 - 1087
• Main Authors: van Esbroeck, Annelot C. M., Janssen, Antonius P. A., Cognetta, 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 American Association for the Advancement of Science 09.06.2017; The American Association for the Advancement of Science
• Subjects: Amides; Amidohydrolases - antagonists & inhibitors; Analgesics - adverse effects; Analgesics - chemistry; Analgesics - metabolism; Analgesics - pharmacology; Anatomy; Anti-Anxiety Agents - adverse effects; Anti-Anxiety Agents - chemistry; Anti-Anxiety Agents - metabolism; Anti-Anxiety Agents - pharmacology; Anxiety; Brain damage; Brain injury; Cannabinoids; 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; Drugs; Fatty acids; Fatty-acid amide hydrolase; Humans; Hydrolase; Inhibitors; Lipase; Lipid metabolism; Metabolism; Nervous system; Networks; Neurological Impairments; Neurons; Neurons - drug effects; Neurons - metabolism; Neurotoxicity; Pain; Protein Interaction Maps; Proteins; Proteomics; Pyridazines - pharmacology; Pyridazines - therapeutic use; Pyridines - adverse effects; Pyridines - chemistry; Pyridines - metabolism; Pyridines - pharmacology; Therapeutic applications; Tissue analysis; Urea - analogs & derivatives; Urea - pharmacology; Urea - therapeutic use
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aaf7497

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.