瓦博格效应
糖酵解
癌细胞
癌症
小分子
癌症研究
生物
细胞生长
HEK 293细胞
细胞培养
计算生物学
化学
生物化学
酶
遗传学
作者
Minsuh Seo,Jeong Do Kim,David Neau,Inder Sehgal,Yong Hwan Lee
出处
期刊:PLOS ONE
[Public Library of Science]
日期:2011-09-21
卷期号:6 (9): e24179-e24179
被引量:73
标识
DOI:10.1371/journal.pone.0024179
摘要
Cancer cells adopt glycolysis as the major source of metabolic energy production for fast cell growth. The HIF-1-induced PFKFB3 plays a key role in this adaptation by elevating the concentration of Fru-2,6-BP, the most potent glycolysis stimulator. As this metabolic conversion has been suggested to be a hallmark of cancer, PFKFB3 has emerged as a novel target for cancer chemotherapy. Here, we report that a small molecular inhibitor, N4A, was identified as an initial lead compound for PFKFB3 inhibitor with therapeutic potential. In an attempt to improve its potency, we determined the crystal structure of the PFKFB3•N4A complex to 2.4 Å resolution and, exploiting the resulting molecular information, attained the more potent YN1. When tested on cultured cancer cells, both N4A and YN1 inhibited PFKFB3, suppressing the Fru-2,6-BP level, which in turn suppressed glycolysis and, ultimately, led to cell death. This study validates PFKFB3 as a target for new cancer therapies and provides a framework for future development efforts.
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