Development of Isoform-Selective Small Molecule Inhibitors of Facilitative Glucose Transporters for Treatment of Glucose Dependent Diseases

Paul Hruz, Washington University School of Medicine

Facilitative glucose transporters serve critical roles in cellular growth and energy homeostasis. To date, 14 human isoforms have been identified, each with specific tissue distribution, substrate preference, kinetic properties, and susceptibility profiles to known inhibitors. Using a robust high throughput screening platform, several novel small molecules with inhibitory potency against human and parasite glucose transporters have been identified for use in treating fatty liver disease, cancer, and malaria. Structure-assisted medical chemistry optimization is being pursued to increase compound potency, isoform-selectivity, and favorable pharmacokinetic properties. Validation of in vitro and in vivo efficacy and early stage safety testing is being performed using established and proprietary reagents, cell-based assays, and animal model systems. Taken together, this work is providing a solid foundation for lead compound identification for human drug development. Identified compounds also have utility as research tools to elucidate normal and maladaptive functions of this important family of membrane glycoproteins.

Host: Kevin Moeller

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