Identification of a novel GLUT1 inhibitor with in vitro and in vivo anti-tumor activity

Abstract

Glucose transporter (GLUT) is a group of membrane proteins which transport extracellular glucoses into cytoplasm, amongst GLUT1 is widely up-regulated in tumor cells. However, no FDA approved GLUT drug has been developed. In this study, we synthesized and identified a novel GLUT1 inhibitor (SMI277) based on in vitro assays and in vivo experiments. Compared with a known GLUT1 inhibitor, SMI277 showed stronger inhibitory activity to glucose uptake, and the inhibition was increased by 40 %. Lactate secretions were decreased by SMI277 in a dose dependent manner. SMI277 was able to inhibit cell proliferations and induce apoptosis of tumor cells. Compared to that of the control group, the tumor growth in mouse model with the administration of 10 mg/kg SMI277 was significantly alleviated and the tumor size was reduced by 58 % on day 21 after inoculation. Interestingly, SMI277 could negatively regulate the expression of GLUT1 protein. Ex vivo experiments showed that SMI277 was capable to enhance CD8⁺ T cell response. Residues Q283, F379 and E380 were identified as contact residues for GLUT1/SMI277 interactions by mutagenesis based binding affinity measurement. In conclusion, SMI277 appeared to be a good lead compound for drug development with specific GLUT1⁺ cancer treatment.

Keywords: Anti-tumor activity; GLUT1 inhibitor; Glucose metabolism.