6HVI

Human PFKFB3 in complex with a N-Aryl 6-Aminoquinoxaline inhibitor 2

6HVI の概要

• エントリーDOI: 10.2210/pdb6hvi/pdb
• 分子名称: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, 8-[3-(dimethylamino)phenyl]-~{N}-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine, PYROPHOSPHATE 2-, ... (7 entities in total)
• 機能のキーワード: kinase, complex, metabolism, cancer, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 60816.96

構造登録者

Banaszak, K.,Sowinska, M.,Gondela, A.,Fabritius, C.H.,Nowak, M. (登録日: 2018-10-11, 公開日: 2018-11-14, 最終更新日: 2024-05-15)

主引用文献

Boutard, N.,Bialas, A.,Sabiniarz, A.,Guzik, P.,Banaszak, K.,Biela, A.,Bien, M.,Buda, A.,Bugaj, B.,Cieluch, E.,Cierpich, A.,Dudek, L.,Eggenweiler, H.M.,Fogt, J.,Gaik, M.,Gondela, A.,Jakubiec, K.,Jurzak, M.,Kitlinska, A.,Kowalczyk, P.,Kujawa, M.,Kwiecinska, K.,Les, M.,Lindemann, R.,Maciuszek, M.,Mikulski, M.,Niedziejko, P.,Obara, A.,Pawlik, H.,Rzymski, T.,Sieprawska-Lupa, M.,Sowinska, M.,Szeremeta-Spisak, J.,Stachowicz, A.,Tomczyk, M.M.,Wiklik, K.,Wloszczak, L.,Ziemianska, S.,Zarebski, A.,Brzozka, K.,Nowak, M.,Fabritius, C.H.
Discovery and Structure-Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors.
ChemMedChem, 14:169-181, 2019

PubMed Abstract: 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 IC of 14 nm for the target and an IC 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.

PubMed: 30378281
DOI: 10.1002/cmdc.201800569

実験手法

X-RAY DIFFRACTION (1.96 Å)