Targeting the sugar metabolism of tumors with a first-in-class 6-phosphofructo-2-kinase (PFKFB4) inhibitor
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Jason Chesney1,2, Jennifer Clark1, Lilibeth Lanceta1, John O. Trent1,2 and Sucheta Telang1,2,3
1 Division of Hematology/Oncology, Department of Medicine, J. Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
2 Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA
3 Department of Pediatrics, University of Louisville, Louisville, KY, USA
Sucheta Telang, email:
Keywords: glycolysis, 6-phosphofructo-2-kinase, fructose-2, 6-bisphosphate, tumor metabolism
Received: April 26, 2015 Accepted: June 02, 2015 Published: June 19, 2015
Human tumors exhibit increased glucose uptake and metabolism as a result of high demand for ATP and anabolic substrates and this metabolotype is a negative prognostic indicator for survival. Recent studies have demonstrated that cancer cells from several tissue origins and genetic backgrounds require the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4), a regulatory enzyme that synthesizes an allosteric activator of glycolysis, fructose-2,6-bisphosphate. We report the discovery of a first-in-class PFKFB4 inhibitor, 5-(n-(8-methoxy-4-quinolyl)amino)pentyl nitrate (5MPN), using structure-based virtual computational screening. We find that 5MPN is a selective inhibitor of PFKFB4 that suppresses the glycolysis and proliferation of multiple human cancer cell lines but not non-transformed epithelial cells in vitro. Importantly, 5MPN has high oral bioavailability and per os administration of a non-toxic dose of 5MPN suppresses the glucose metabolism and growth of tumors in mice.
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