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Discovery and Structure-Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors.

Authors :
Boutard N
Białas A
Sabiniarz A
Guzik P
Banaszak K
Biela A
Bień M
Buda A
Bugaj B
Cieluch E
Cierpich A
Dudek Ł
Eggenweiler HM
Fogt J
Gaik M
Gondela A
Jakubiec K
Jurzak M
Kitlińska A
Kowalczyk P
Kujawa M
Kwiecińska K
Leś M
Lindemann R
Maciuszek M
Mikulski M
Niedziejko P
Obara A
Pawlik H
Rzymski T
Sieprawska-Lupa M
Sowińska M
Szeremeta-Spisak J
Stachowicz A
Tomczyk MM
Wiklik K
Włoszczak Ł
Ziemiańska S
Zarębski A
Brzózka K
Nowak M
Fabritius CH
Source :
ChemMedChem [ChemMedChem] 2019 Jan 08; Vol. 14 (1), pp. 169-181. Date of Electronic Publication: 2018 Dec 06.
Publication Year :
2019

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 <subscript>50</subscript> of 14 nm for the target and an IC <subscript>50</subscript> 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.<br /> (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Details

Language :
English
ISSN :
1860-7187
Volume :
14
Issue :
1
Database :
MEDLINE
Journal :
ChemMedChem
Publication Type :
Academic Journal
Accession number :
30378281
Full Text :
https://doi.org/10.1002/cmdc.201800569