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

• Published in: Oncotarget Vol. 6; no. 20; pp. 18001 - 18011
• Main Authors: Chesney, Jason, Clark, Jennifer, Lanceta, Lilibeth, Trent, John O, Telang, Sucheta
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 20-07-2015
• Subjects: Administration, Oral; Aminoquinolines - administration & dosage; Aminoquinolines - chemistry; Aminoquinolines - pharmacokinetics; Aminoquinolines - pharmacology; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biological Availability; Carcinoma, Lewis Lung - drug therapy; Carcinoma, Lewis Lung - enzymology; Carcinoma, Lewis Lung - genetics; Carcinoma, Lewis Lung - pathology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - 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; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice, Inbred C57BL; Mice, Knockout; Molecular Structure; Molecular Targeted Therapy; Nitrates - administration & dosage; Nitrates - chemistry; Nitrates - pharmacokinetics; Nitrates - pharmacology; Phosphofructokinase-2 - antagonists & inhibitors; Phosphofructokinase-2 - genetics; Phosphofructokinase-2 - metabolism; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Research Paper; RNA Interference; Structure-Activity Relationship; Transfection; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; 6-bisphosphate; 6-phosphofructo-2-kinase; tumor metabolism; glycolysis; fructose-2
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.4534

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.