BIOCHEMISTRY
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. —PAK
Science, this issue p. 1084