Discovery and Structure-Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors.

Energy and biomass production in cancer cell is largely supported by aerobic glycolysis in what is called the "Warburg effect". The process is regulated by key enzymes among which phosphofructokinase PFK-2 plays a significant role by producing fructose-2,6-biphosphate, the most potent activator of the glycolysis rate limiting step performed by phosphofructokinase PFK-1. We report herein the synthesis, biological evaluation and structure-activity relationship of novel inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), the ubiquitous and hypoxia-induced isoform of PFK-2. X-Ray crystallography and docking were instrumental in the design and optimization of a N-aryl 6-aminoquinoxaline series. The most potent representative, compound 69, displayed a 14 nM IC50 on target, and a 0.49 μM IC50 of fructose-2,6-biphosphate production in human colon carcinoma HCT116 cells. This work provides a new entry in the field of PFKFB3 inhibitors with potential for development in oncology.