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 Hendriks, Luciano 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
Author Information
Annelot C M van Esbroeck: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. ORCID
Antonius P A Janssen: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. ORCID
Armand B Cognetta: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA. ORCID
Daisuke Ogasawara: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA. ORCID
Guy Shpak: Department of Psychiatry, Erasmus University Medical Centre, 3000 CA, Rotterdam, Netherlands. ORCID
Mark van der Kroeg: Department of Psychiatry, Erasmus University Medical Centre, 3000 CA, Rotterdam, Netherlands. ORCID
Vasudev Kantae: Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. ORCID
Marc P Baggelaar: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. ORCID
Femke M S de Vrij: Department of Psychiatry, Erasmus University Medical Centre, 3000 CA, Rotterdam, Netherlands.
Hui Deng: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. ORCID
Marco Allarà: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche (CNR), Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Italy. ORCID
Filomena Fezza: Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy. ORCID
Zhanmin Lin: Department of Neuroscience, Erasmus Medical Centre, 3000 CA, Rotterdam, Netherlands. ORCID
Tom van der Wel: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. ORCID
Marjolein Soethoudt: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. ORCID
Elliot D Mock: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. ORCID
Hans den Dulk: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. ORCID
Ilse L Baak: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. ORCID
Bogdan I Florea: Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands.
Luciano De Petrocellis: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche (CNR), Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Italy. ORCID
Herman S Overkleeft: Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. ORCID
Thomas Hankemeier: Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. ORCID
Chris I De Zeeuw: Department of Neuroscience, Erasmus Medical Centre, 3000 CA, Rotterdam, Netherlands.
Vincenzo Di Marzo: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche (CNR), Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Italy. ORCID
Mauro Maccarrone: European Centre for Brain Research-Institute for Research and Healthcare (IRCCS) Santa Lucia Foundation, Via del Fosso del Fiorano 65, 00143 Rome, Italy. ORCID
Benjamin F Cravatt: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA. ORCID
Steven A Kushner: Department of Psychiatry, Erasmus University Medical Centre, 3000 CA, Rotterdam, Netherlands. m.van.der.stelt@chem.leidenuniv.nl s.kushner@erasmusmc.nl. ORCID
Mario van der Stelt: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. m.van.der.stelt@chem.leidenuniv.nl s.kushner@erasmusmc.nl. ORCID
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.
References
Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14694-9
[PMID: 10611275]
