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Discovery and Structure–Activity Relationships of N‐Aryl 6‐Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors
ChemMedChem ( IF 3.4 ) Pub Date : 2018-12-06 , DOI: 10.1002/cmdc.201800569
Nicolas Boutard 1 , Arkadiusz Białas 1 , Aleksandra Sabiniarz 1 , Paweł Guzik 1 , Katarzyna Banaszak 1 , Artur Biela 1 , Marcin Bień 1, 2 , Anna Buda 1 , Barbara Bugaj 1 , Ewelina Cieluch 1 , Anna Cierpich 1, 3 , Łukasz Dudek 1 , Hans‐Michael Eggenweiler 4 , Joanna Fogt 1 , Monika Gaik 1, 5 , Andrzej Gondela 1 , Krzysztof Jakubiec 1 , Mirek Jurzak 6 , Agata Kitlińska 1 , Piotr Kowalczyk 1 , Maciej Kujawa 1 , Katarzyna Kwiecińska 1, 7 , Marcin Leś 1 , Ralph Lindemann 8 , Monika Maciuszek 1, 9 , Maciej Mikulski 1 , Paulina Niedziejko 1 , Alicja Obara 1 , Henryk Pawlik 1 , Tomasz Rzymski 1 , Magdalena Sieprawska‐Lupa 1 , Marta Sowińska 1 , Joanna Szeremeta‐Spisak 1 , Agata Stachowicz 1 , Mateusz M. Tomczyk 1, 10 , Katarzyna Wiklik 1 , Łukasz Włoszczak 1, 11 , Sylwia Ziemiańska 1 , Adrian Zarębski 1 , Krzysztof Brzózka 1 , Mateusz Nowak 1 , Charles‐Henry Fabritius 1
Affiliation  

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 μm 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.

中文翻译:

N-芳基6-氨基喹喔啉作为有效的PFKFB3激酶抑制剂的发现与构效关系

癌细胞的能量和生物质生产在很大程度上被有氧糖酵解所支持,这就是所谓的Warburg效应。该过程受关键酶的调节,其中磷酸果糖激酶PFK-2通过产生果糖-2,6-二磷酸而起重要作用。磷酸果糖激酶PFK-1执行的最有效的糖酵解限速步骤激活剂。本文介绍了6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酯酶3(PFKFB3)的新型抑制剂的合成,生物学评估以及其结构与活性之间的关系,PFKFB3是一种普遍存在且由低氧引起的PFK-2亚型,被报道。X射线晶体学和对接有助于设计和优化一系列N-芳基6-氨基喹喔啉。最有力的代表,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,目标物的IC 50为14 n m,0.4的IC 50为0.49μm m为人类结肠癌HCT116细胞中果糖2,6-二磷酸的产生。这项工作为PFKFB3抑制剂领域的发展提供了新的机会。
更新日期:2018-12-06
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