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 3rd; 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

doi:10.1126/science.aaf7497

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

Science. 2017 Jun 9;356(6342):1084-1087. doi: 10.1126/science.aaf7497.

Authors

Annelot C M van Esbroeck¹, Antonius P A Janssen¹, Armand B Cognetta 3rd², Daisuke Ogasawara², Guy Shpak³, Mark van der Kroeg³, Vasudev Kantae⁴, Marc P Baggelaar¹, Femke M S de Vrij³, Hui Deng¹, Marco Allarà⁵, Filomena Fezza⁶, Zhanmin Lin⁷, Tom van der Wel¹, Marjolein Soethoudt¹, Elliot D Mock¹, Hans den Dulk¹, Ilse L Baak¹, Bogdan I Florea⁸, Giel Hendriks⁹, Luciano De Petrocellis⁵, Herman S Overkleeft⁸, Thomas Hankemeier⁴, Chris I De Zeeuw^{7

10}, Vincenzo Di Marzo⁵, Mauro Maccarrone^{11

12}, Benjamin F Cravatt², Steven A Kushner¹³, Mario van der Stelt¹⁴

Affiliations

¹ Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands.
² Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Department of Psychiatry, Erasmus University Medical Centre, 3000 CA, Rotterdam, Netherlands.
⁴ Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands.
⁵ Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche (CNR), Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Italy.
⁶ Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy.
⁷ Department of Neuroscience, Erasmus Medical Centre, 3000 CA, Rotterdam, Netherlands.
⁸ Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands.
⁹ Toxys B.V., Robert Boyleweg 4, 2333 CG, Leiden, Netherlands.
¹⁰ Netherlands Institute for Neuroscience, Royal Dutch Academy of Arts and Sciences, 1105 BA, Amsterdam, Netherlands.
¹¹ European Centre for Brain Research-Institute for Research and Healthcare (IRCCS) Santa Lucia Foundation, Via del Fosso del Fiorano 65, 00143 Rome, Italy.
¹² Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy.
¹³ Department of Psychiatry, Erasmus University Medical Centre, 3000 CA, Rotterdam, Netherlands. [email protected] [email protected].
¹⁴ Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. [email protected] [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Analgesics
Anti-Anxiety Agents
BIA 10-2474
Cyclic N-Oxides
N-pyridazin-3-yl-4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)piperidine-1-carboxamide
Pyridazines
Pyridines
Urea
Amidohydrolases
fatty-acid amide hydrolase

Grants and funding

R01 DA033760/DA/NIDA NIH HHS/United States