Targeting the sugar metabolism of tumors with a first-in-class 6-phosphofructo-2-kinase (PFKFB4) inhibitor

// Jason Chesney 1,2 , Jennifer Clark 1 , Lilibeth Lanceta 1 , John O. Trent 1,2 and Sucheta Telang 1,2,3 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 Correspondence to: Sucheta Telang, email: // Keywords : glycolysis, 6-phosphofructo-2-kinase, fructose-2, 6-bisphosphate, tumor metabolism Received : Apil 26, 2015 Accepted : June 02, 2015 Published : June 19, 2015 Abstract 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.