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Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes

journal contribution
posted 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.

History

Journal

Nature chemical biology

Volume

10

Issue

2

Pagination

113 - 121

Publisher

Nature Publishing Group

Location

New York, N.Y.

eISSN

1552-4469

Language

eng

Publication classification

C Journal article; C1 Refereed article in a scholarly journal

Copyright notice

2014, Nature America, Inc.