Inhibition of eEF2-K by thieno[2,3-b]pyridine analogues

Lockman, Jeffrey W.; Reeder, Matthew D.; Suzuki, Kazuyuki; Ostanin, Kirill; Hoff, R. John; Bhoite, Leena; Austin, Harry; Baichwal, Vijay; Willardsen, J. Adam

doi:10.1016/j.bmcl.2010.02.005

Cited by 56 publications

(49 citation statements)

References 13 publications

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“…Rottlerin ( 2 ) is a nonspecific inhibitor of multiple protein kinases (63, 64). The thieno[2,3-b]pyridine ( 3 ) is an ATP-competitive inhibitor of eEF-2K that lacks potency in cells (39). The mechanism of inhibition of NH125 ( 4 ), which was first identified as a histidine kinase inhibitor (50, 65) and later as an inhibitor of eEF-2K (40) has not been determined.…”

Section: Figurementioning

confidence: 99%

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Investigating the Kinetic Mechanism of Inhibition of Elongation Factor 2 Kinase by NH125: Evidence of a Common in Vitro Artifact

et al. 2012

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Evidence is emerging that elongation factor 2 kinase (eEF-2K) has potential as a target for anti-cancer therapy and possibly for the treatment of depression. Here the steady-state kinetic mechanism of eEF-2K is presented using a peptide substrate and is shown to conform to an ordered sequential mechanism with ATP binding first. Substrate inhibition by the peptide was observed and revealed to be competitive with ATP, explaining the observed ordered mechanism. Several small molecules are reported to inhibit eEF-2K activity with the most notable being the histidine kinase inhibitor NH125, which has been used in a number of studies to characterize eEF-2K activity in cells. While NH125 was previously reported to inhibit eEF-2K in vitro with an IC50 of 60 nM its mechanism of action was not established. Using the same kinetic assay the ability of an authentic sample of NH125 to inhibit eEF-2K was assessed over a range of substrate and inhibitor concentrations. A typical dose-response curve for the inhibition of eEF-2K by NH125 is best fit to an IC50 of 18 ± 0.25 µM and a Hill coefficient of 3.7 ± 0.14, suggesting that NH125 is a weak inhibitor of eEF-2K under the experimental conditions of a standard in vitro kinase assay. To test the possibility that NH125 is a potent inhibitor of eEF2 phosphorylation we assessed its ability to inhibit the phosphorylation of eEF2. Under standard kinase assay conditions NH125 exhibits similar weak ability to inhibit the phosphorylation of eEF2 by eEF-2K. Notably, the activity of NH125 is severely abrogated by the addition of 0.1 % triton to the kinase assay through a process that can be reversed upon dilution. These studies suggest that NH125 is as a non-specific colloidal aggregator in vitro, a notion further supported by the observation that NH125 inhibits other protein kinases, such as ERK2 and TRPM7 in a similar manner to eEF-2K. As NH125 is reported to inhibit eEF-2K in a cellular environment its ability to inhibit eEF2 phosphorylation was assessed in MDA-MB-231 breast cancer, A549 lung cancer and HEK-293T cell lines using a Western blot approach. No sign of decrease in the level of eEF2 phosphorylation was observed up to 12 hours following addition of NH125 to the media. Furthermore, contrary to the previously reported literatures, NH125 induced the phosphorylation of eEF-2.

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Section: Figurementioning

confidence: 99%

“…These include the 1,3-selenazine derivative (1) (37), rottlerin (2) (34, 38) the thieno[2,3-b]pyridine derivative (3) (39) and the histidine kinase inhibitor NH125 (4) (40). NH125 has been used by a number of investigators to investigate eEF-2K activity in cell cultures (40–44).…”

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confidence: 99%

Investigating the Kinetic Mechanism of Inhibition of Elongation Factor 2 Kinase by NH125: Evidence of a Common in Vitro Artifact

et al. 2012

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“…The aforementioned biological activities stimulated our interest for the synthesis of several new condensed heterocyclic compounds containing thieno [2,3-b] pyridine moiety condensed with each of pyridine, cyclopentyl, tetrahydroquinoline, pyrimidine, 1,6-naphthiridin, benzofuro [2,3-b] pyridine, imidazo [1,2-c] pyrimidine, [1,2,3] triazolo [1,5-a] pyrimidine. The new condensed heterocyclic derivatives possessing latent functional substituents appear promising to fulfill the objectives of our biological activity studies and the desired chemical transformations.…”

Section: Introductionmentioning

confidence: 99%

Utility of thieno[2,3-b] pyridine derivatives in the synthesis of some condensed heterocyclic compounds with expected biological activity

Hassan¹,

Sarg²,

Said³

et al. 2013

Univers Org Chem

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“…The thieno [2,3-b]pyridine derivatives occupy special place and have attracted considerable attention because of their broad pharmacological activities, including anticancer [1][2][3][4][5][6][7][8][9], antiviral [10][11][12][13], anti-inflammatory [14][15][16][17], antimicrobial [18,19], antidiabetic [20][21][22][23], antihypertensive [24][25][26] and osteogenic [27,28] activities, in addition to treatment of CNS disorders [29][30][31]. Also, pyridine derivatives of different heterocyclic nucleus have shown potent pharmacological properties like antifungal [32,33], antitubercular [34], antibacterial [35], antimicrobial [36], insecticida [37].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of some new Thieno[2,3-b]pyridines, Pyrimidino[4',5':4,5]thieno[2,3-b]pyridine and Pyridines Incorporating 5-Bromobenzofuran-2-yl Moiety

2015

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2-Sulfanyl-6-(2-thienyl)pyridine-3-carbonitrile, 1-Amino-6-(5-bromo-benzofuran-2-yl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile, thieno [2,3-b]pyridins, pyrimidino[4',5':4,5] thieno [2,3-b]pyridine, quinazoline and carbamate derivatives were synthesized from sodium 3-(5-bromobenzofuran-2-yl)-3-oxoprop-1-en-1-olate with. The newly synthesized compounds were elucidated by elemental analysis, spectral data, and alternative synthesis whenever possible and chemical transportation.

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Inhibition of eEF2-K by thieno[2,3-b]pyridine analogues

Cited by 56 publications

References 13 publications

Investigating the Kinetic Mechanism of Inhibition of Elongation Factor 2 Kinase by NH125: Evidence of a Common in Vitro Artifact

Investigating the Kinetic Mechanism of Inhibition of Elongation Factor 2 Kinase by NH125: Evidence of a Common in Vitro Artifact

Utility of thieno[2,3-b] pyridine derivatives in the synthesis of some condensed heterocyclic compounds with expected biological activity

Synthesis of some new Thieno[2,3-b]pyridines, Pyrimidino[4',5':4,5]thieno[2,3-b]pyridine and Pyridines Incorporating 5-Bromobenzofuran-2-yl Moiety

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