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

 描述（由申请人提供）：本项目的目标是抵消瓦尔堡效应的影响（即，异常高的葡萄糖利用率特征的癌细胞）对下游糖基化终点的影响，其有助于致癌进展和耐药性。抑制糖酵解以治疗性解决瓦尔堡效应的一般方法在过去几年中受到越来越多的关注，大多数尝试集中在抑制葡萄糖摄入细胞或随后进入能量处理途径。相比之下，该项目采取了不同的策略，涉及靶向己糖胺生物合成途径中糖酵解下游的酶。通过抑制该途径，UDP-GlcNAc的水平降低，我们预测这将直接降低两种促癌生化机制（特别是核胞质蛋白和细胞表面半乳糖凝集素晶格的O-GlcNAc修饰），并间接减缓另一种促癌生物化学机制（用于细胞增殖的“构件”的生物合成）。 癌症干细胞标志物的产生）。这些原理验证实验的成功完成将为急需的新型癌症药物的动物和临床转化提供基础。

 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.