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.
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