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

Abstract

Dietary flavonoids inhibit certain protein- 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 cellsignals. 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.

Analysis of inositol phosphate metabolism by capillary electrophoresis electrospray ionization mass spectrometry

“…2c ). We additionally analyzed the effect of a recently identified IP6K inhibitor: quercetin (Q) 28 reduced 5-PP-InsP 5 levels in both HCT116 NIH and HCT116 NIH PPIP5K1,2 − / − cells by 50–60% (Fig. 2c ).…”

Inositol Pyrophosphates: Signaling Molecules with Pleiotropic Actions in Mammals

“…The development of animal models for cell-type-specific deletions in IP6Ks and PPIP5Ks will expand our understanding of the in vivo roles of PP-IPs. The in-parallel development of pharmacological reagents is also needed to investigate effects on acute inhibition of IP6Ks, PPIP5Ks, or other upstream inositol polyphosphate kinases, such as IPMK [91][92][93]. Recently, Shears and colleagues discovered quercetin and its derivative as IP6K-specific inhibitors [92].…”

“…The in-parallel development of pharmacological reagents is also needed to investigate effects on acute inhibition of IP6Ks, PPIP5Ks, or other upstream inositol polyphosphate kinases, such as IPMK [91][92][93]. Recently, Shears and colleagues discovered quercetin and its derivative as IP6K-specific inhibitors [92]. Since IP kinases can play non-catalytic roles, selective suppression of catalytic activities of IP6Ks and PPIP5Ks will allow us to focus on their PP-IP-dependent signaling actions.…”

Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases

“…It is also necessary to determine the therapeutic window for each disease. Several groups are working to screen compound libraries against IP6Ks and to exploit subtle differences in active sites of the isotypes to develop potent and isotype-specific IP6K inhibitors [42,[270][271][272]. Hopefully, IP6K inhibitors, either alone or in combination, will emerge as new drugs to treat metabolic diseases.…”