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

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.