Targeting the sugar metabolism of tumors with a first-in-class 6-phosphofructo-2-kinase (PFKFB4) inhibitor.
Targeting the sugar metabolism of tumors with a first-in-class 6-phosphofructo-2-kinase (PFKFB4) inhibitor.
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DOI：
10.18632/oncotarget.4534
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发表时间：
2015-07-20
期刊：
影响因子：
--
通讯作者：
Telang S
中科院分区：
文献类型：
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作者：
Chesney J;Clark J;Lanceta L;Trent JO;Telang S
由于对ATP和合成代谢底物的高需求，人类肿瘤表现出葡萄糖摄取和代谢增加，并且这种代谢型是生存的负面预后指标。最近的研究表明，来自几种组织来源和遗传背景的癌细胞需要表达6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶4（PFKFB 4），这是一种合成糖酵解变构激活剂果糖-2，6-二磷酸的调节酶。我们报告了使用基于结构的虚拟计算筛选发现的一类PFKFB 4抑制剂，5-（n-（8-甲氧基-4-喹啉基）氨基）戊基硝酸酯（5 MPN）。我们发现5 MPN是PFKFB 4的选择性抑制剂，其抑制多种人类癌细胞系的糖酵解和增殖，但不抑制体外非转化上皮细胞。重要的是，5 MPN具有高口服生物利用度，并且口服施用无毒剂量的5 MPN抑制小鼠中的葡萄糖代谢和肿瘤生长。
Human tumors exhibit increased glucose uptake and metabolism as a result of high demand for ATP and anabolic substrates and this metabolotype is a negative prognostic indicator for survival. Recent studies have demonstrated that cancer cells from several tissue origins and genetic backgrounds require the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4), a regulatory enzyme that synthesizes an allosteric activator of glycolysis, fructose-2,6-bisphosphate. We report the discovery of a first-in-class PFKFB4 inhibitor, 5-(n-(8-methoxy-4-quinolyl)amino)pentyl nitrate (5MPN), using structure-based virtual computational screening. We find that 5MPN is a selective inhibitor of PFKFB4 that suppresses the glycolysis and proliferation of multiple human cancer cell lines but not non-transformed epithelial cells in vitro. Importantly, 5MPN has high oral bioavailability and per os administration of a non-toxic dose of 5MPN suppresses the glucose metabolism and growth of tumors in mice.