Discovery and Structure-Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors
Discovery and Structure-Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors
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DOI：
10.1002/cmdc.201800569
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发表时间：
2019-01-08
期刊：
影响因子：
3.4
通讯作者：
Fabritius, Charles-Henry
中科院分区：
文献类型：
--
作者：
Boutard, Nicolas;Bialas, Arkadiusz;Fabritius, Charles-Henry
癌细胞中的能量和生物量生产主要由有氧糖酵解支持，这就是所谓的瓦尔堡效应。该过程由关键酶调节，其中磷酸果糖激酶PFK-2通过产生果糖-2，6-二磷酸起着重要作用;磷酸果糖激酶PFK-1进行的糖酵解限速步骤的最有效激活剂。本文报道了新型6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶3（PFKFB 3）抑制剂的合成、生物学评价和构效关系。X-射线晶体学和对接有助于一系列N-芳基6-氨基喹喔啉的设计和优化。最有效的代表，N-（4-甲磺酰基吡啶-3-基）-8-（3-甲基-1-苯并噻吩-5-基）喹喔啉-6-胺，显示出对靶点的IC 50为14 nm，对人结肠癌HCT 116细胞中果糖-2，6-二磷酸产生的IC 50为0.49 μ m。这项工作为PFKFB 3抑制剂领域提供了一个新的入口，具有在肿瘤学中开发的潜力。
Energy and biomass production in cancer cells are largely supported by aerobic glycolysis in what is called the Warburg effect. The process is regulated by key enzymes, among which phosphofructokinase PFK-2 plays a significant role by producing fructose-2,6-biphosphate; the most potent activator of the glycolysis rate-limiting step performed by phosphofructokinase PFK-1. Herein, the synthesis, biological evaluation and structure-activity relationship of novel inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which is the ubiquitous and hypoxia-induced isoform of PFK-2, are reported. X-ray crystallography and docking were instrumental in the design and optimisation of a series of N-aryl 6-aminoquinoxalines. The most potent representative, N-(4-methanesulfonylpyridin-3-yl)-8-(3-methyl-1-benzothiophen-5-yl)quinoxalin-6-amine, displayed an IC50 of 14 nm for the target and an IC50 of 0.49 mu m for fructose-2,6-biphosphate production in human colon carcinoma HCT116 cells. This work provides a new entry in the field of PFKFB3 inhibitors with potential for development in oncology.