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 proteomicmethods 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.

Van Esbroeck, A., Janssen, A., Cognetta, A.b., Ogasawara, D., Shpak, G., Van Der Kroeg, M., et al. (2017). Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. SCIENCE, 356(6342), 1084-1087 [10.1126/science.aaf7497].

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

Fezza F.;Maccarrone M.;
2017-01-01

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 proteomicmethods 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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10
English
Amidohydrolases; Analgesics; Anti-Anxiety Agents; Cell Line, Tumor; Clinical Trials, Phase I as Topic; Cross Reactions; Cyclic N-Oxides; Humans; Neurons; Protein Interaction Maps; Pyridazines; Pyridines; Urea
http://science.sciencemag.org/content/sci/356/6342/1084.full.pdf
Van Esbroeck, A., Janssen, A., Cognetta, A.b., Ogasawara, D., Shpak, G., Van Der Kroeg, M., et al. (2017). Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. SCIENCE, 356(6342), 1084-1087 [10.1126/science.aaf7497].
Van Esbroeck, Acm; Janssen, Apa; Cognetta, Ab; Ogasawara, D; Shpak, G; Van Der Kroeg, M; Kantae, V; Baggelaar, Mp; De Vrij, Fms; Deng, H; Allara, M; Fezza, F; Lin, Z; Van Der Wel, T; Soethoudt, M; Mock, Ed; Den Dulk, H; Baak, Il; Florea, Bi; Hendriks, G; De Petrocellis, L; Overkleeft, Hs; Hankemeier, T; De Zeeuw, Ci; Di Marzo, V; Maccarrone, M; Cravatt, Bf; Kushner, Sa; Van Der Stelt, M
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
van Esbroeck et al., 2017 Science.pdf

non disponibili

Tipologia: Versione Editoriale (PDF)
Licenza: Copyright dell'editore
Dimensione 626.78 kB
Formato Adobe PDF
626.78 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/227296
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 208
  • ???jsp.display-item.citation.isi??? 198
social impact