PFKFB3 inhibitors as potential anticancer agents: mechanisms of action, current developments, and structure-activity relationships

Abstract Cancer cells adopt aerobic glycolysis as the major source of energy and biomass production for fast cell proliferation. The bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), plays a crucial role in the regulation of glycolysis by controlling the steady-state cytoplasmic levels of fructose-2,6-bisphosphate (F2,6BP), which is the most potent allosteric activator of 6-phosphofructo-1-kinase (PFK-1), a key rate-limiting enzyme of glycolysis. Therefore, selective inhibition of PFKFB3 has gained substantial interest as an attractive strategy for cancer therapy. In recent years, numerous class PFKFB3 inhibitors have been disclosed, and emerging trends such as the availability of PFKFB3 crystal structures, structure-based screening strategies and diverse functional assays are improving optimization and development of original leads. Herein, we review the structure and function of PFKFB3 as well as the representative small-molecule inhibitors, in particular emphasis on their chemical structures, pharmacological properties, selectivity, binding modes and structure-activity relationships (SARs).