title: Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes.
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.
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Eduardo
authors.identifier: 0000000333595867
authors.initials: E
authors.lastname: Dominguez
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Galmozzi
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Chang
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Ku-Lung
authors.initials: KL
authors.lastname: Hsu
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Pawlak
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Godio
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Partida
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Sherry
authors.initials: S
authors.lastname: Niessen
authors.affiliation: Centre for Obesity Research and Education-Monash University, The Alfred Hospital, Prahran, Australia.
authors.forename: Paul E
authors.initials: PE
authors.lastname: O'Brien
authors.affiliation: Centre for Physical Activity and Nutrition Research School of Exercise and Nutrition Sciences, Deakin University, Burwood, Australia.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Russell
authors.affiliation: Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, Victoria, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Enrique
authors.initials: E
authors.lastname: Saez
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000235:genetics*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D055808:Drug Discovery; D051379:Mice; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D040081:Protein Array Analysis; D040901:Proteomics; D054852:Small Molecule Libraries
chemical_list: D054852:Small Molecule Libraries; C121305:CES1P1 protein, human; D002265:Carboxylic Ester Hydrolases