ChemMedChem p. 169 - 181 (2019)
Update date:2022-08-11
Topics:
Boutard, Nicolas
Bia?as, Arkadiusz
Sabiniarz, Aleksandra
Guzik, Pawe?
Banaszak, Katarzyna
Biela, Artur
Bień, Marcin
Buda, Anna
Bugaj, Barbara
Cieluch, Ewelina
Cierpich, Anna
Dudek, ?ukasz
Eggenweiler, Hans-Michael
Fogt, Joanna
Gaik, Monika
Gondela, Andrzej
Jakubiec, Krzysztof
Jurzak, Mirek
Kitlińska, Agata
Kowalczyk, Piotr
Kujawa, Maciej
Kwiecińska, Katarzyna
Le?, Marcin
Lindemann, Ralph
Maciuszek, Monika
Mikulski, Maciej
Niedziejko, Paulina
Obara, Alicja
Pawlik, Henryk
Rzymski, Tomasz
Sieprawska-Lupa, Magdalena
Sowińska, Marta
Szeremeta-Spisak, Joanna
Stachowicz, Agata
Tomczyk, Mateusz M.
Wiklik, Katarzyna
W?oszczak, ?ukasz
Ziemiańska, Sylwia
Zar?bski, Adrian
Brzózka, Krzysztof
Nowak, Mateusz
Fabritius, Charles-Henry
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.
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