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: Jason Chesney, Jennifer Clark, Lilibeth Lanceta, John O Trent, Sucheta Telang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 20 Pg. 18001-11 (Jul 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26221874 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 5-(n-(8-methoxy-4-quinolyl)amino)pentyl nitrate
• Aminoquinolines
• Antineoplastic Agents
• Nitrates
• PFKFB4 protein, human
• Pfkfb4 protein, rat
• Protein Kinase Inhibitors
• Phosphofructokinase-2

Topics

• Administration, Oral
• Aminoquinolines (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Biological Availability
• Carcinoma, Lewis Lung (drug therapy, enzymology, genetics, pathology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, genetics, pathology)
• Cell Proliferation (drug effects)
• Computer-Aided Design
• Dose-Response Relationship, Drug
• Female
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Glycolysis (drug effects)
• HCT116 Cells
• Humans
• Lung Neoplasms (drug therapy, enzymology, genetics, pathology)
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Structure
• Molecular Targeted Therapy
• Nitrates (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Phosphofructokinase-2 (antagonists & inhibitors, genetics, metabolism)
• Protein Kinase Inhibitors (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• RNA Interference
• Structure-Activity Relationship
• Transfection
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays