Fig. 1
DRB18 is a pan-GLUT inhibitor with multi-GLUT and multi-cancer targeting potential. DRB18 is a lead compound derived from WZB117. It was tested in 9 different cancer types in the NCI60 cell line panel. The protein structure for hGLUT1 was generated using homology modeling from the crystal structure of hGLUT3 PDB-ID 5C65 for the docking study. All values are relative to controls. Filled arrows indicate extremely sensitive cancer types to DRB18 compared with WZB117 and unfilled arrows indicate cancer types with mildly improved potency of DRB18 compared with WZB117. Assay values represented are mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001. a Structure of WZB117 and DRB18. b DRB18 reduced cell viability in three cancer cell lines after 72 h of treatment in a dose-dependent manner in a resazurin assay. c NCI for screening result for anticancer potency of WZB117 and DRB18 in their NCI60 cell line panel. It shows, treated by either WZB117 or DRB18, the number of cancer cell lines in the total number of cancer cell lines in a given cancer type (M/N) that exhibit IC50 values lower than 10 μM. The screening was conducted with a cell viability MTT assay at NCI. d The IC50 determination of DRB18’s glucose uptake inhibitory activity in four different HEK293 cell lines each expressing a single GLUT. e DRB18 binds to hGLUT1 binding pocket in outward open conformation. DRB18 forms hydrogen bonds (Asn 411), π-π interactions (Phe 26 and Phe 379), and halogen bonds (Asn 288) with different residues in hGLUT1. The protein is shown with the cytoplasmic side down. Hydrogen bonds and Halogen bonds are shown in broken yellow and purple lines. π-π interactions are shown in broken blue lines. The specific elements are shown in the respective colors with oxygen in red; nitrogen in blue and hydrogen in white. Carbons in DRB18 are shown in yellow and chlorine in dark green. f The correlation between the glidescores of DRB18 in hGLUT1-4 docking study (as shown in e) and the glucose uptake assay results (IC50s in d), The correlation coefficient was calculated to be R2 = 0.8577