6ibz
Human PFKFB3 in complex with a N-Aryl 6-Aminoquinoxaline inhibitor 7
Structural highlights
FunctionF263_HUMAN Synthesis and degradation of fructose 2,6-bisphosphate. Publication Abstract from PubMedIn oncology, the "Warburg effect" describes the elevated production of energy by glycolysis in cancer cells. The ubiquitous and hypoxia-induced 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a noteworthy role in the regulation of glycolysis by producing fructose-2,6-biphosphate (F-2,6-BP), a potent activator of the glycolysis rate-limiting phosphofructokinase PFK-1. Series of amides and sulfonamides derivatives based on a N-aryl 6-aminoquinoxaline scaffold were synthesized and tested for their inhibition of PFKFB3 in vitro in a biochemical assay as well as in HCT116 cells. The carboxamide series displayed satisfactory kinetic solubility and metabolic stability, and within this class, potent lead compounds with low nanomolar activity have been identified with a suitable profile for further in vivo evaluation. Synthesis of amide and sulfonamide substituted N-aryl 6-aminoquinoxalines as PFKFB3 inhibitors with improved physicochemical properties.,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 HM, 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 MM, Wiklik K, Wloszczak L, Ziemianska S, Zarebski A, Brzozka K, Nowak M, Fabritius CH Bioorg Med Chem Lett. 2019 Feb 15;29(4):646-653. doi: 10.1016/j.bmcl.2018.12.034., Epub 2018 Dec 16. PMID:30626557[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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