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ACS Chem Biol. 2019 Feb 15;14(2):192-197. doi: 10.1021/acschembio.8b01097. Epub 2019 Jan 31.

Global Portrait of Protein Targets of Metabolites of the Neurotoxic Compound BIA 10-2474.

Author information

1
Medicine Design, Chemical Biology , Pfizer Worldwide Research and Development , 1 Portland Street , Cambridge , Massachusetts 02139 , United States.
2
Department of Chemistry, The Skaggs Institute for Chemical Biology , The Scripps Research Institute , La Jolla , California 92037 , United States.
3
Medicine Design, Medicinal Chemistry , Pfizer Worldwide Research and Development , Eastern Point Road , Groton , Connecticut 06340 , United States.
4
Medicine Design, Pharmacokinetics, Dynamics and Metabolism , Pfizer Worldwide Research and Development , Eastern Point Road , Groton , Connecticut 06340 , United States.
5
Medicine Design, Pharmacokinetics, Dynamics and Metabolism , Pfizer Worldwide Research and Development , 1 Portland Street , Cambridge , Massachusetts 02139 , United States.

Abstract

Clinical investigation of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 resulted in serious adverse neurological events. Structurally unrelated FAAH inhibitors tested in humans have not presented safety concerns, suggesting that BIA 10-2474 has off-target activities. A recent activity-based protein profiling (ABPP) study revealed that BIA 10-2474 and one of its major metabolites inhibit multiple members of the serine hydrolase class to which FAAH belongs. Here, we extend these studies by performing a proteome-wide analysis of covalent targets of BIA 10-2474 metabolites. Using alkynylated probes for click chemistry-ABPP in human cells, we show that des-methylated metabolites of BIA 10-2474 covalently modify the conserved catalytic cysteine in aldehyde dehydrogenases, including ALDH2, which has been implicated in protecting the brain from oxidative stress-related damage. These findings indicate that BIA 10-2474 and its metabolites have the potential to inhibit multiple mechanistically distinct enzyme classes involved in nervous system function.

PMID:
30702848
PMCID:
PMC6383364
[Available on 2020-02-15]
DOI:
10.1021/acschembio.8b01097

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