| Title : Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474 - van Esbroeck_2017_Science_356_1084 |
| Author(s) : van Esbroeck ACM , Janssen APA , Cognetta AB, 3rd , 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 |
| Ref : Science , 356 :1084 , 2017 |
|
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. |
| PubMedSearch : van Esbroeck_2017_Science_356_1084 |
| PubMedID: 28596366 |
| Inhibitor | BIA-10-2474 |
van Esbroeck ACM, Janssen APA, Cognetta AB, 3rd, 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 (2017)
Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474
Science
356 :1084
van Esbroeck ACM, Janssen APA, Cognetta AB, 3rd, 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 (2017)
Science
356 :1084