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

Annelot C M van Esbroeck, Antonius P A Janssen, Armand B Cognetta, Daisuke Ogasawara, Guy Shpak, Mark van der Kroeg, Vasudev Kantae, Marc P Baggelaar, Femke M S de Vrij, Hui Deng, Marco Allarà, Filomena Fezza, Zhanmin Lin, Tom van der Wel, Marjolein Soethoudt, Elliot D Mock, Hans den Dulk, Ilse L Baak, Bogdan I Florea, Giel HendriksLuciano De Petrocellis, Herman S Overkleeft, Thomas Hankemeier, Chris I De Zeeuw, Vincenzo Di Marzo, Mauro Maccarrone, Benjamin F Cravatt, Steven A Kushner, Mario van der Stelt

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)1084-1087
Number of pages4
JournalScience (New York, N.Y.)
Issue number6342
Publication statusPublished - 9 Jun 2017
Externally publishedYes


  • Amidohydrolases/antagonists & inhibitors
  • Analgesics/adverse effects
  • Anti-Anxiety Agents/adverse effects
  • Cell Line, Tumor
  • Clinical Trials, Phase I as Topic
  • Cross Reactions
  • Cyclic N-Oxides/adverse effects
  • Humans
  • Neurons/drug effects
  • Protein Interaction Maps
  • Pyridazines/pharmacology
  • Pyridines/adverse effects
  • Urea/analogs & derivatives


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