2. Academic Validation
  3. Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis

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.
Chunfang Gu 1,  Michael A Stashko 2,  Ana C Puhl-Rubio 2,  Molee Chakraborty 3,  Anutosh Chakraborty 3,  Stephen V Frye 2,  Kenneth H Pearce 2,  Xiaodong Wang 2,  Stephen B Shears 1,  Huanchen Wang 1
Affiliations

Affiliations

  • 1 Inositol Signaling Group, Signal Transduction Laboratory , National Institute of Environmental Health Sciences , Research Triangle Park , North Carolina 27709 , United States.
  • 2 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.
  • 3 Department of Pharmacology and Physiology , Saint Louis University School of Medicine , M370, Schwitalla Hall, 1402 South Grand Boulevard , Saint Louis , Missouri 63104 , United States.
PMID: 30624931 DOI: 10.1021/acs.jmedchem.8b01593
Abstract

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.

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