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Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474, SCIENCE, 2017

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.

Esbroeck A.C.M. van, Janssen A.P.A., Cognetta A.B. III et. al.
09 June 2017
DOI link
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