Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3

J Med Chem. 2015 Apr 23;58(8):3611-25. doi: 10.1021/acs.jmedchem.5b00352. Epub 2015 Apr 13.


A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.

MeSH terms

  • Administration, Oral
  • Animals
  • Cell Line
  • Drug Design*
  • Humans
  • Male
  • Mice
  • Models, Molecular
  • Phosphofructokinase-2 / antagonists & inhibitors*
  • Phosphofructokinase-2 / chemistry
  • Phosphofructokinase-2 / metabolism*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Rats, Wistar
  • Structure-Activity Relationship


  • Protein Kinase Inhibitors
  • PFKFB3 protein, human
  • Phosphofructokinase-2