Identification of Rapaglutin E as an Isoform-Specific Inhibitor of Glucose Transporter 1

Natural products rapamycin and FK506 are macrocyclic compounds with therapeutic benefits whose unique scaffold inspired the generation and exploration of hybrid macrocycle rapafucins. From this library, a potent inhibitor of the facilitative glucose transporter (GLUT), rapaglutin A (RgA), was previously identified. RgA is a pan-GLUT inhibitor of Class I isoforms GLUT1, GLUT3, and GLUT4. Herein, we report the discovery of rapaglutin E (RgE). Unlike RgA, RgE is highly specific for GLUT1. Further characterization revealed that RgE and RgA likely bound to distinct sites on GLUT1 despite their shared FKBP-binding domain, suggesting that the distinct effector domains of RgE and RgA play key roles in the recognition of GLUTs.