title: Phenotypic screening to identify small-molecule enhancers for glucose uptake: target identification and rational optimization of their efficacy.
abstract: Small-molecule glucose uptake enhancers targeted to myotubes and adipocytes were developed through a phenotypic screening linked with target identification and rational optimization. The target protein of glucose-uptake enhancers was identified as a nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma). Subsequent optimization of initial hits generated lead compounds with high potency for PPARγ transactivation and cellular glucose uptake. Finally, we confirmed that the chirality of optimized ligands differentiates their PPARγ transcriptional activity, binding affinity, and inhibitory activity toward Cdk5 (cyclin-dependent kinase 5)-mediated phosphorylation of PPARγ at Ser273. Using phenotype-based lead discovery along with early-stage target identification, this study has identified a new small-molecule enhancer of glucose uptake that targets PPARγ.
authors.affiliation: Department of Chemistry, Seoul National University, Seoul 151-747 (Korea).
authors.forename: Minseob
authors.initials: M
authors.lastname: Koh
authors.forename: Jongmin
authors.initials: J
authors.lastname: Park
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Koo
authors.forename: Donghyun
authors.initials: D
authors.lastname: Lim
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Cha
authors.forename: Ala
authors.initials: A
authors.lastname: Jo
authors.forename: Jang Hyun
authors.initials: JH
authors.lastname: Choi
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D005947:Glucose / Q000378:metabolism*; D051379:Mice; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D047495:PPAR gamma; D005947:Glucose
keywords: PPARγ; drug discovery; glucose uptake; phenotypic screening; target identification