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Cited by 56Flavonoids in Medical ResearchSynthesis of Organic CompoundsComputational Drug Discovery Methods

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

Gu, Chunfang, Stashko, Michael A., Puhl-Rubio, Ana C., Chakraborty, Molee, Chakraborty, Anutosh, Frye, Stephen V., Pearce, Kenneth H., Wang, Xiaodong +2 more·2019·Journal of Medicinal Chemistry
DOI 10.1021/acs.jmedchem.8b01593PMC PMC6467728
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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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Authors
Gu, C., Stashko, M. A., Puhl-Rubio, A. C., Chakraborty, M., Chakraborty, A., Frye, S. V., Pearce, K. H., Wang, X., Shears, S. B., & Wang, H.
Affiliations
  • National Institutes of Health (US)
  • University of North Carolina at Chapel Hill (US)
  • 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
  • Saint Louis University (US)
Corresponding author
  • Shears, Stephen B.
  • Wang, Huanchen
ORCID
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2019-01-09
Volume
62
Issue
3
Pages
1443-1454
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/acs.jmedchem.8b01593
PMC
PMC6467728
OpenAlex
W4229692339
Cited by
56
References
0
Citations by year
2026: 2 · 2025: 8 · 2024: 6 · 2023: 10 · 2022: 6 · 2021: 13 · 2020: 9 · 2019: 2
FWCI
4.80
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders
  • National Institute of Environmental Health Sciences
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK103746, R01 DK101645)
Topics
  • Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
  • Health Sciences › Medicine › Pharmacology › Synthesis of Organic Compounds
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords
inositol polyphosphate kinase, inositol hexakisphosphate kinase, inositol polyphosphate multikinase, quercetin, flavonoids, diosmetin, kinase inhibition, structure-activity relationship, ATP binding site, protein-ligand interactions, HCT116 cells, gastrointestinal tract, inositol phosphate signaling, dietary flavonoids

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