Cells that are rapidly proliferating or hypoxic emphasize glycolysis over oxidative phosphorylation to meet energy needs. During glycolysis, fructose 6-phosphate (F6P) is phosphorylated by 6-phosphofructo-2-kinases (PFKs) to generate fructose 2,6-bisphosphate. As PFK family members also mediate the reverse reaction as fructose 2,6-bisphosphatases, these enzymes are known as PFKFB family members. Notably, PFKFB3 is overexpressed in a wide variety of cancer cell lines. YZ9 is a potent inhibitor of PFKFB3, with an IC50 value of 183 nM in vitro. It avidly competes with F6P at PFKFB3 (Ki = 94 nM). YZ9 is also cell permeable, inhibiting the growth of HeLa cells with a GI50 value of 2.7 μM.
