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PFKFB3 inhibitors act on a kinase that produces a key allosteric activator of glycolysis. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) synthesizes fructose-2,6-bisphosphate, which in turn activates the glycolytic enzyme phosphofructokinase 1. Among the four family isoforms, PFKFB3 has the highest ratio of kinase to phosphatase activity. 3PO was reported in 2008 as a small molecule that lowers glycolytic flux by inhibiting PFKFB3. A 2013 study showed that PFKFB3-driven glycolysis controls vessel sprouting by endothelial cells. PFK15, its derivative PFK-158, KAN0438757 and AZ-PFKFB3-67 are other listed inhibitors. PFKFB4-IN-1 and 5MPN target the related isoform PFKFB4, which is also studied in tumor metabolism.
