title: Targeting the sugar metabolism of tumors with a first-in-class 6-phosphofructo-2-kinase (PFKFB4) inhibitor.
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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, J. Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.|Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Chesney
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, J. Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Clark
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, J. Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Lilibeth
authors.initials: L
authors.lastname: Lanceta
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, J. Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.|Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA.
authors.forename: John O
authors.initials: JO
authors.lastname: Trent
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, J. Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.|Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA.|Department of Pediatrics, University of Louisville, Louisville, KY, USA.
authors.forename: Sucheta
authors.initials: S
authors.lastname: Telang
mesh_terms: D000284:Administration, Oral; D000634:Aminoquinolines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009566:Nitrates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D034622:RNA Interference; D013329:Structure-Activity Relationship; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000607692:5-(n-(8-methoxy-4-quinolyl)amino)pentyl nitrate; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D009566:Nitrates; C506672:PFKFB4 protein, human; C542952:Pfkfb4 protein, rat; D047428:Protein Kinase Inhibitors; D025481:Phosphofructokinase-2
keywords: 6-bisphosphate; 6-phosphofructo-2-kinase; fructose-2; glycolysis; tumor metabolism