DiscussionWe have identified a novel series of small molecule inhibitors of GLUT1 that ablate the uptake of [3H]Deoxy-D-Glucose (2-DG) and the extrusion of lactate from cancer cells leading to apoptotic cancer cell death. These molecules are currently being developed as novel anti-tumorigenic agents.
The transporter GLUT1 plays a major role in glucose uptake into cancer cells, enabling rapid proliferation. Elevated GLUT1 expression is prevalent in many cancers and GLUT1 function is used to image tumours utilising the glucose mimetic FDG in FDG PET. GLUT1 inhibitors were identified using a cell-based assay to measure uptake of 2-DG in cells transfected to express human GLUT1. In vitro cell-based experiments confirmed the series was competitive with glucose and did not cause haemolysis of red blood cells, a theoretical side effect of a GLUT1 inhibitor. Chemical optimisation resulted in significant improvements in activity with molecules demonstrating potencies down to 10 nM and clear selectivity over related transporters. The GLUT1 inhibitors ablated 2-DG uptake and extracellular lactate extrusion in cancer cells. Exposure of a variety of cancer cell lines to exemplar compounds led to cell death in a glucose-dependent manner. These compounds are highly drug-like with good pharmacokinetic profiles. In vivo efficacy studies are underway and the series is being optimised for pre-clinical candidate selection.