Phenotypic Screening to Identify Small-Molecule Enhancers for Glucose Uptake: Target Identification and Rational Optimization of Their Efficacy

초록

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 PPAR (peroxisome proliferator-activated receptor gamma). Subsequent optimization of initial hits generated lead compounds with high potency for PPAR transactivation and cellular glucose uptake. Finally, we confirmed that the chirality of optimized ligands differentiates their PPAR transcriptional activity, binding affinity, and inhibitory activity toward Cdk5 (cyclin-dependent kinase 5)-mediated phosphorylation of PPAR 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 PPAR.

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