Use of Protein Kinase–Focused Compound Libraries for the Discovery of New Inositol Phosphate Kinase Inhibitors

Puhl-Rubio, Ana C.; Stashko, Michael A.; Wang, Huanchen; Hardy, P Brian; Tyagi, Vikas; Li, Bing; Wang, Xiaodong; Kireev, Dmitri; Jessen, Henning J.; Frye, Stephen V.; Shears, Stephen B.; Pearce, Kenneth H.

doi:10.1177/2472555218775323

Cited by 17 publications

(21 citation statements)

References 20 publications

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“…We began this work by investigating if 2 is an inhibitor of hIP6K2. As in our earlier study of hIP6K2 activity 7 , we used a time-resolved fluorescence resonance energy transfer (TR-FRET) assay in 384-well microplate format, using as substrates 10 μM InsP 6 and 10 μM ATP. It should be noted that these assays all contained 0.01% Brij-35.…”

Section: Introductionmentioning

confidence: 99%

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

Stashko

Puhl-Rubio

et al. 2019

J. Med. Chem.

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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.

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Section: Introductionmentioning

confidence: 99%

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

Stashko

Puhl-Rubio

et al. 2019

J. Med. Chem.

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“…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.…”

Section: Can Ip6k Inhibitors Be Used To Treat Metabolic Diseases?mentioning

confidence: 99%

Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases

2020

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In mammals, a family of three inositol hexakisphosphate kinases (IP6Ks) synthesizes the inositol pyrophosphate 5-IP7 from IP6. Genetic deletion of Ip6k1 protects mice from high fat diet induced obesity, insulin resistance and fatty liver. IP6K1 generated 5-IP7 promotes insulin secretion from pancreatic β-cells, whereas it reduces insulin signaling in metabolic tissues by inhibiting the protein kinase Akt. Thus, IP6K1 promotes high fat diet induced hyperinsulinemia and insulin resistance in mice while its deletion has the opposite effects. IP6K1 also promotes fat accumulation in the adipose tissue by inhibiting the protein kinase AMPK mediated energy expenditure. Genetic deletion of Ip6k3 protects mice from age induced fat accumulation and insulin resistance. Accordingly, the pan IP6K inhibitor TNP [N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates obesity, insulin resistance and fatty liver in diet induced obese mice by improving Akt and AMPK mediated insulin sensitivity and energy expenditure. TNP also protects mice from bone loss, myocardial infarction and ischemia reperfusion injury. Thus, the IP6K pathway is a potential target in obesity and other metabolic diseases. Here, we summarize the studies that established IP6Ks as a potential target in metabolic diseases. Further studies will reveal whether inhibition of this pathway has similar pleiotropic benefits on metabolic health of humans.

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“…IP6K1 can attach phosphate to a range of myo-inositol phosphates that are phosphorylated at positions 1 and 5, producing a series of inositol pyrophosphates among which diphosphoinositol pentakisphosphate (IP7) is the most important. N2-(m-(trifluoromethyl)benzyl) N6-(p-nitrobenzyl)purine (TNP), an inhibitor that is not subtype-specific, is used as a tool compound; and IP6K2 inhibitors have most recently been reported [5]. Takeda now claims IP6K inhibitors, focusing on diabetes and cardiac failure -but they are also not subtype-specific: the majority inhibits all enzyme subtypes at a 100 nM concentration.…”

Section: Wo/2018/178304mentioning

confidence: 99%