6HVH

Human PFKFB3 in complex with a N-Aryl 6-Aminoquinoxaline inhibitor 1

Summary for 6HVH

• Entry DOI: 10.2210/pdb6hvh/pdb
• Descriptor: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, 3-[[8-(1-methylindol-6-yl)quinoxalin-6-yl]amino]-~{N}-(oxan-4-yl)pyridine-4-carboxamide, PYROPHOSPHATE 2-, ... (6 entities in total)
• Functional Keywords: kinase, complex, metabolism, cancer, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 60797.88

Authors

Banaszak, K.,Jakubiec, K.,Bialas, A.,Fabritius, C.H.,Nowak, M. (deposition date: 2018-10-11, release date: 2018-11-14, Last modification date: 2024-05-15)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.36 Å)