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

Dominguez, Eduardo, Galmozzi, Andrea, Chang, Jae Won, Hsu, Ku-Lung, Pawlak, Joanna, Li, Weiwei, Godio, Cristina, Thomas, Jason, Partida, David, Niessen, Sherry, O'Brien, Paul E., Russell, Aaron P., Watt, Matthew J., Nomura, Daniel K., Cravatt, Benjamin F. and Saez, Enrique 2014, Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes, Nature chemical biology, vol. 10, no. 2, pp. 113-121, doi: 10.1038/nchembio.1429.

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Title Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes
Author(s) Dominguez, Eduardo
Galmozzi, Andrea
Chang, Jae Won
Hsu, Ku-Lung
Pawlak, Joanna
Li, WeiweiORCID iD for Li, Weiwei
Godio, Cristina
Thomas, Jason
Partida, David
Niessen, Sherry
O'Brien, Paul E.
Russell, Aaron P.ORCID iD for Russell, Aaron P.
Watt, Matthew J.
Nomura, Daniel K.
Cravatt, Benjamin F.
Saez, Enrique
Journal name Nature chemical biology
Volume number 10
Issue number 2
Start page 113
End page 121
Total pages 11
Publisher Nature Publishing Group
Place of publication New York, N. Y.
Publication date 2014-02
ISSN 1552-4469
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Summary 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.
Language eng
DOI 10.1038/nchembio.1429
Field of Research 111699 Medical Physiology not elsewhere classified
Socio Economic Objective 920106 Endocrine Organs and Diseases (excl. Diabetes)
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2014, Nature America, Inc.
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