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Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes
journal contributionposted on 01.02.2014, 00:00 authored by E Dominguez, A Galmozzi, J W Chang, K L Hsu, J Pawlak, W Li, C Godio, J Thomas, D Partida, S Niessen, P E O'Brien, Aaron RussellAaron Russell, M J Watt, D K Nomura, B F Cravatt, E Saez
Phenotypic screening is making a comeback in drug discovery as the maturation of chemical proteomics methods has facilitated target identification for bioactive small molecules. A limitation of these approaches is that time-consuming genetic methods or other means are often required to determine the biologically relevant target (or targets) from among multiple protein-compound interactions that are typically detected. Here, we have combined phenotypic screening of a directed small-molecule library with competitive activity-based protein profiling to map and functionally characterize the targets of screening hits. Using this approach, we identify carboxylesterase 3 (Ces3, also known as Ces1d) as a primary molecular target of bioactive compounds that promote lipid storage in adipocytes. We further show that Ces3 activity is markedly elevated during adipocyte differentiation. Treatment of two mouse models of obesity-diabetes with a Ces3 inhibitor ameliorates multiple features of metabolic syndrome, illustrating the power of the described strategy to accelerate the identification and pharmacologic validation of new therapeutic targets.
JournalNature chemical biology
Pagination113 - 121
PublisherNature Publishing Group
LocationNew York, N.Y.
Publication classificationC Journal article; C1 Refereed article in a scholarly journal
Copyright notice2014, Nature America, Inc.
Read the peer-reviewed publication
AnimalsCarboxylic Ester HydrolasesCells, CulturedDiabetes MellitusDisease Models, AnimalDrug Delivery SystemsDrug DiscoveryMiceObesityPhenotypeProtein Array AnalysisProteomicsSmall Molecule LibrariesScience & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyDECREASES BLOOD-LIPIDSPPAR-GAMMA EXPRESSIONSERINE HYDROLASESCOMPLEX PROTEOMESTRIACYLGLYCEROLLIPASEMETABOLISMINHIBITORSPROTEINSTARGET