Novel small molecule, WZB117, competitively inhibit GLUT1‐mediated glucose transport to halt cancer growth

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GLUT1‐mediated cellular glucose transport is required to fuel anaerobic metabolism in proliferating cancer cells. Accordingly, GLUT1 inhibition by small molecules is a viable strategy to halt the proliferation of cancers. However, GLUT1 is presently not targeted therapeutically in cancers because of lack of potent and specific inhibitors. Recently, a novel small molecule, WZB117, was shown to kill lung and breast cancer cells by inhibiting GLUT1‐mediated glucose transport, without affecting non‐tumorigenic cells. Here, we studied the detailed kinetics of WZB117 inhibition of GLUT1, and found that WZB117 inhibits uptake of the non‐metabolizable sugar, 3‐O‐methylglucose, by red blood cells with an inhibition constant of 2.83 μM. Our data show that WZB117 is a competitive inhibitor of GLUT1‐mediated zero‐trans sugar uptake and exchange transport but is a non‐competitive inhibitor of zero‐trans exit. These results, together with our docking studies, suggest that WZB117 binds at or near the exofacial sugar‐binding site of GLUT1. In addition, our preliminary data on the specificity of WZB117 for GLUT1 suggests that, while WZB117 inhibits GLUT1 with a high affinity, it is also a potent inhibitor of the skeletal muscle and adipose specific transporter GLUT4 and the neuronal glucose transporter GLUT3. We conclude that the ability of WZB117 to serve as a tumor‐specific inhibitor derives, not from specificity of transport inhibition but rather, from the absolute dependence of tumor cells on anaerobic metabolism and glucose‐dependent anabolism.Support or Funding InformationThis work is supported by NIH grant DK 44888.