I dentification of a novel small‐molecule allosteric inhibitor of glucose transporter type 5 for treating fructose‐induced diseases

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Glucose transporter type 5 (GLUT5) is a major molecule that transports fructose in mammals. Fructose has become a major constituent of our modern diet and been implicated as an underlying cause of metabolic diseases such as diabetes, obesity, and nonalcoholic fatty liver disease. In addition, certain cancer cells have been found to utilize fructose via the GLUT5-dependent pathway for their survival. Moreover, mutations in the ALDOB gene cause hereditary fructose intolerance, a condition in which individuals experience hypoglycemia upon fructose intake. These results suggest that limiting fructose utilization by inhibiting GLUT5 may be a novel therapeutic strategy for treating fructose-induced diseases. In this study, we report the identification of a potent, selective, and orally available small-molecule inhibitor of GLUT5. Through high-throughput screening and subsequent compound optimization, we identified compound S-700. S-700 exhibited a potent inhibitory effect on fructose uptake in human GLUT5- and mouse GLUT5-overexpressed Chinese hamster ovary cells with IC50 values of 59 and 28 nM, respectively. The in vitro analysis showed that S-700 allosterically binds to GLUT5 independent of the fructose binding site. In contrast, S-700 did not inhibit human GLUT1; GLUT1 inhibition should be avoided as it impairs the brain function. Single oral administration of S-700 (0.03–1 mg/kg) potently inhibited GLUT5-mediated fructose uptake in the gut during an oral fructose tolerance test in rats. Notably, the predose of S-700 (1 mg/kg) up to 24 h before a fructose dose was highly effective in inducing this effect, indicating the durable effect of S-700. We further assessed the effects of chronic oral administration of S-700 (0.1–3 mg/kg/day) on liver triglyceride (TG) accumulation in Western Diet (D12079B)-fed rats. S-700 (0.3–3 mg/kg) potently suppressed TG levels in the liver and improved the abnormal liver weight of these animals. The therapeutic potential of S-700 (0.3–3 mg/kg/day) in decreasing liver TG levels was similar to or more potent than that of PF-06835919 (30 mg/kg/day), a ketohexokinase inhibitor blocking liver fructose metabolism. In addition, S-700 (0.3–3 mg/kg) increased glucagon-like peptide 1 secretion, reduced food intake, and decreased body weight in Western Diet-fed rats without causing abnormal changes during the study. Finally, S-700 (3 mg/kg) completely prevented fructose-induced hypoglycemia in Aldob knockout mice, a model of hereditary fructose intolerance. Taken together, these results suggest that S-700 is a novel drug candidate for treating fructose-induced diseases.