Small-molecule inhibitors of glucose transporters

Facilitative glucose transporters (GLUTs) encoded by the SLC2A genes mediate the initial steps of sugar utilization in cells. Fourteen existing GLUT family members are classified into three subclasses based on the characteristics of the gene structure. Several GLUT isoforms, especially GLUT1 and GLUT3, are overexpressed in many tumors, and their high expression correlates with poor clinical outcomes in patients. Altered energy metabolism, such as increased glycolysis, is a critical hallmark of most human cancers. Therefore, small-molecule GLUT inhibitors are promising bioprobes for understanding complex tumor metabolism and may serve as new candidate drugs for cancer therapy. Certain naturally occurring flavonoids have been shown to inhibit glucose uptake by GLUTs. Recently, a variety of potent and selective GLUT inhibitors of different chemotypes have been developed to target glycolysis-addicted tumors. Moreover, the elucidation of GLUT crystal structures has enabled high-throughput virtual screening to identify GLUT isoform-specific inhibitors. In this chapter, we provide an overview of small-molecule GLUT inhibitors, ranging from natural products to natural product-inspired and synthetic compounds.