Targeting the Warburg Effect in cancer; relationships for 2-arylpyridazinones as inhibitors of the key glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3)

Bioorg Med Chem. 2014 Feb 1;22(3):1029-39. doi: 10.1016/j.bmc.2013.12.041. Epub 2013 Dec 30.


High-throughput screening of a small-molecule library identified a 5-triazolo-2-arylpyridazinone as a novel inhibitor of the important glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3). Such inhibitors are of interest due to PFKFB3's control of the important glycolytic pathway used by cancer cells to generate ATP. A series of analogues was synthesized to study structure-activity relationships key to enzyme inhibition. Changes to the triazolo or pyridazinone rings were not favoured, but limited-size substitutions on the aryl ring provided modest increases in potency against the enzyme. Selected analogues and literature-described inhibitors were evaluated for their ability to suppress the glycolytic pathway, as detected by a decrease in lactate production, but none of these compounds demonstrated such suppression at non-cytotoxic concentrations.

Keywords: (2,2,6,2-tetramethylpiperidin-1-yl)oxy; 6-phosphofructo-1-kinase; 6-phosphofructo-2-kinase/2,6-bisphosphatase 3; BCA; ECAR; F1,6-BP; F2,6-BP; F6P; Glycolysis; PFK-1; PFKFB3; Pyridazinone; RIPA; TEMPO; Warburg Effect; bicinchoninic acid assay; extracellular acidification rate; fructose-1,6-bisphosphate; fructose-2,6-bisphosphate; fructose-6-phosphate; radioimmunoprecipitation assay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor / drug effects
  • Chemistry Techniques, Synthetic
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Glycolysis / drug effects
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Phosphofructokinase-2 / antagonists & inhibitors*
  • Pyridazines / chemistry
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Pyridazines
  • Small Molecule Libraries
  • pyridazine
  • PFKFB3 protein, human
  • Phosphofructokinase-2