AGX1/2 inhibitors as key modulators of the hexosamine biosynthetic pathway



 DESCRIPTION (provided by applicant): The goal of this project is to counteract the impact of the Warburg effect (i.e., abnormally high glucose utilization characteristic of cancer cells) on downstream glycosylation endpoints that contribute to oncogenic progression and drug resistance. The general approach of inhibiting glycolysis to therapeutically address the Warburg effect has received increasing interest in the past few years with most attempts focused on inhibiting the intake of glucose into a cell or subsequently, into energy processing pathways. By contrast, this project takes a different strategy that involves targeting enzymes found downstream of glycolysis in the hexosamine biosynthetic pathway. By inhibiting this pathway, levels of UDP-GlcNAc are lowered, which we predict will directly reduce two cancer-promoting biochemical mechanisms (specifically O-GlcNAc-modification of nucleocytosolic proteins and the cell surface galectin lattice) and indirect slow another (biosynthesis of "building blocks" for the production of cancer stem cell markers). Successful completion of these proof-of-principle experiments will provide a foundation for the animal and clinical translation of a new class of badly needed cancer drugs.