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

2017; American Association for the Advancement of Science; Volume: 356; Issue: 6342 Linguagem: Inglês

10.1126/science.aaf7497

1095-9203

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,

Pancreatic function and diabetes

A clue to a drug's neurotoxicity? The drug BIA 10-2474 inhibits fatty acid amide hydrolase (FAAH), a lipase that degrades a specific endocannabinoid. On the basis of this activity, BIA 10-2474 was being developed as a potential treatment for anxiety and pain. In a phase 1 trial of the drug, one subject died, and four others suffered brain damage. As an initial step in investigating whether inhibition of off-target proteins by BIA 10-2474 might contribute to its clinical neurotoxicity, van Esbroeck et al. used activity-based proteomic assays to identify proteins targeted by the drug. Studying human cells and brain samples from subjects not associated with the trial, they found that BIA 10-2474 targeted several different lipases in addition to FAAH. It also substantially altered lipid metabolism in cultured neurons. Science , this issue p. 1084