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

Eduardo Dominguez, Andrea Galmozzi, Jaewon Chang, Kulung Hsu, Joanna Pawlak, Weiwei Li, Cristina Godio, Jason R Thomas, David Partida, Sherry M Niessen, Paul Edmond O'Brien, Aaron Paul Russell, Matthew James Watt, Daniel Nomura, Benjamin F Cravatt, Enrique Saez

Research output: Contribution to journalArticleResearchpeer-review

78 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)113 - 121
Number of pages9
JournalNature Chemical Biology
Volume10
Issue number2
DOIs
Publication statusPublished - 2014

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