Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis

J Med Chem. 2019 Feb 14;62(3):1443-1454. doi: 10.1021/acs.jmedchem.8b01593. Epub 2019 Jan 25.


Dietary flavonoids inhibit certain protein kinases and phospholipid kinases by competing for their ATP-binding sites. These nucleotide pockets have structural elements that are well-conserved in two human small-molecule kinases, inositol hexakisphosphate kinase (IP6K) and inositol polyphosphate multikinase (IPMK), which synthesize multifunctional inositol phosphate cell signals. Herein, we demonstrate that both kinases are inhibited by quercetin and 16 related flavonoids; IP6K is the preferred target. Relative inhibitory activities were rationalized by X-ray analysis of kinase/flavonoid crystal structures; this detailed structure-activity analysis revealed hydrophobic and polar ligand/protein interactions, the degree of flexibility of key amino acid side chains, and the importance of water molecules. The seven most potent IP6K inhibitors were incubated with intact HCT116 cells at concentrations of 2.5 μM; diosmetin was the most selective and effective IP6K inhibitor (>70% reduction in activity). Our data can instruct on pharmacophore properties to assist the future development of inositol phosphate kinase inhibitors. Finally, we propose that dietary flavonoids may inhibit IP6K activity in cells that line the gastrointestinal tract.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • HCT116 Cells
  • Humans
  • Inositol Phosphates / metabolism
  • Molecular Structure
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Phosphotransferases (Phosphate Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Phosphate Group Acceptor) / metabolism
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quercetin / chemistry
  • Quercetin / metabolism
  • Quercetin / pharmacology*
  • Structure-Activity Relationship


  • Inositol Phosphates
  • Protein Kinase Inhibitors
  • Quercetin
  • Phosphotransferases (Alcohol Group Acceptor)
  • inositol polyphosphate multikinase
  • Proto-Oncogene Proteins c-akt
  • Phosphotransferases (Phosphate Group Acceptor)
  • inositol hexakisphosphate kinase