EXTH-07. DESIGN AND EVALUATION OF WP1122, AN INHIBITOR OF GLYCOLYSIS WITH INCREASED CNS UPTAKE.

Glioblastoma (GBM), an aggressive primary brain tumor, relies on anaerobic glycolysis to produce energy. A known inhibitor of glycolysis, 2-deoxy-D-glucose (2-DG) has been clinically tested but its poor drug-like characteristics limited its practical application for cancer treatment. To overcome this problem, we have performed latentiation of 2-DG. Chemical modification of biologically active 2-DG led to the formation of prodrugs with improved pharmacokinetic and pharmacodynamic properties and subsequently to selection of the lead compound WP1122 (3,6-di-O-acetyl-2-deoxy-D-glucose). Unlike 2-DG, its prodrug WP1222 enters cells and cross blood-brain barrier by passive diffusion rather than by specific glucose transporter, then undergoes deacetylation by esterases and is trapped inside the cell after phosphorylation at C-6 hydroxyl group. 6-phospho-2-deoxy glucose acts as a competitive inhibitor of hexokinase (HK) blocking phosphorylation of D-glucose and subsequently inhibiting glycolytic pathway. Our in vitro experiments confirmed inhibition of glycolysis in U87 cells and high sensitivity of broad spectrum of cancer cells to WP1122 both in hypoxic and normoxic conditions (IC(50) range from 1–10 mM). In vivo studies showed that WP1122 is well tolerated by animals even with prolonged exposure and extend survival of mice in orthotopic U87 GBM model. Initial pharmacokinetic experiments demonstrated rapid uptake of WP1122 after oral administration allowing to achieve two orders of magnitude higher maximum concentration of 2-DG in plasma, compared to animals treated with an equal molar dose of pure 2-DG. We also observed significantly higher levels of 2-DG in brains of mice treated with WP1122 than in mice receiving equal dose of 2-DG. In summary, WP1122 is a biologically effective prodrug of 2-DG with a good toxicity profile and promising pharmacokinetic characteristics that warrants detail preclinical and clinical development as a potential therapeutic agent for glioblastomas and other highly glycolytic tumors.