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Nat Chem Biol. 2014 Feb;10(2):113-21. doi: 10.1038/nchembio.1429. Epub 2013 Dec 22.

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

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Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
Centre for Obesity Research and Education-Monash University, The Alfred Hospital, Prahran, Australia.
Centre for Physical Activity and Nutrition Research School of Exercise and Nutrition Sciences, Deakin University, Burwood, Australia.
Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, Victoria, Australia.


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.

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