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; Shears, Stephen B.; Wang, Huanchen

doi:10.1021/acs.jmedchem.8b01593

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

Journal Article · Tue Jan 08 23:00:00 EST 2019 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b01593· OSTI ID:1502197

Gu, Chunfang ^[1]; Stashko, Michael A. ^[2]; Puhl-Rubio, Ana C. ^[2]; Chakraborty, Molee ^[3]; Chakraborty, Anutosh ^[3]; ^[2]; Pearce, Kenneth H. ^[2]; ^[2]; ^[1]; Wang, Huanchen ^[1]

National Inst. of Environmental Health Sciences (NIEHS), Research Triangle Park, NC (United States)
Univ. of North Carolina, Chapel Hill, NC (United States)
Saint Louis Univ. School of Medicine, MO (United States)

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 $$μ$$M; diosmetin was the most selective and effective IP6K inhibitor (>70% reduction in activity). Overall, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); National Institute of Environmental Health Sciences (NIEHS)

OSTI ID:: 1502197

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 3 Vol. 62; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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