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

  • Oncotarget. 2015 Jul 20;6(20):18001-11. doi: 10.18632/oncotarget.4534.
Jason Chesney  1  2 ,  Jennifer Clark  1 ,  Lilibeth Lanceta  1 ,  John O Trent  1  2 ,  Sucheta Telang  1  2  3
Affiliations
  • 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.
PMID: 26221874 DOI: 10.18632/oncotarget.4534
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.

Keywords
6-bisphosphate; 6-phosphofructo-2-kinase; fructose-2; glycolysis; tumor metabolism.
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