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Identification of a new membrane-permeable inhibitor against inositol-1,4,5-trisphosphate-3-kinase A

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Identification of a new membrane-permeable inhibitor against inositol-1,4,5-trisphosphate-3-kinase A. / Schröder, Dominik; Rehbach, Christoph; Seyffarth, Carola; Neuenschwander, Martin; Kries, Jens V; Windhorst, Sabine.

in: BIOCHEM BIOPH RES CO, Jahrgang 439, Nr. 2, 20.09.2013, S. 228-34.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Schröder, D, Rehbach, C, Seyffarth, C, Neuenschwander, M, Kries, JV & Windhorst, S 2013, 'Identification of a new membrane-permeable inhibitor against inositol-1,4,5-trisphosphate-3-kinase A', BIOCHEM BIOPH RES CO, Jg. 439, Nr. 2, S. 228-34. https://doi.org/10.1016/j.bbrc.2013.08.053

APA

Schröder, D., Rehbach, C., Seyffarth, C., Neuenschwander, M., Kries, J. V., & Windhorst, S. (2013). Identification of a new membrane-permeable inhibitor against inositol-1,4,5-trisphosphate-3-kinase A. BIOCHEM BIOPH RES CO, 439(2), 228-34. https://doi.org/10.1016/j.bbrc.2013.08.053

Vancouver

Schröder D, Rehbach C, Seyffarth C, Neuenschwander M, Kries JV, Windhorst S. Identification of a new membrane-permeable inhibitor against inositol-1,4,5-trisphosphate-3-kinase A. BIOCHEM BIOPH RES CO. 2013 Sep 20;439(2):228-34. https://doi.org/10.1016/j.bbrc.2013.08.053

Bibtex

@article{c575d7c8bb32403aad1549c835996f01,
title = "Identification of a new membrane-permeable inhibitor against inositol-1,4,5-trisphosphate-3-kinase A",
abstract = "Ectopic expression of the neuron-specific inositol-1,4,5-trisphosphate-3-kinase A (ITPKA) in lung cancer cells increases their metastatic potential because the protein exhibits two actin regulating activities; it bundles actin filaments and regulates inositol-1,4,5-trisphosphate (InsP3)-mediated calcium signals by phosphorylating InsP3. Thus, in order to inhibit the metastasis-promoting activity of ITPKA, both its actin bundling and its InsP3kinase activity has to be blocked. In this study, we performed a high throughput screen in order to identify specific and membrane-permeable substances against the InsP3kinase activity. Among 341,44 small molecules, 237 compounds (0.7%) were identified as potential InsP3kinase inhibitors. After determination of IC50-values, the three compounds with highest specificity and highest hydrophobicity (EPPC-3, BAMB-4, MEPTT-3) were further characterized. Only BAMB-4 was nearly completely taken up by H1299 cells and remained stable after cellular uptake, thus exhibiting a robust stability and a high membrane permeability. Determination of the inhibitor type revealed that BAMB-4 belongs to the group of mixed type inhibitors. Taken together, for the first time we identified a highly membrane-permeable inhibitor against the InsP3kinase activity of ITPKA providing the possibility to partly inhibit the metastasis-promoting effect of ITPKA in lung tumor cells.",
keywords = "Cell Line, Tumor, Cell Membrane Permeability, Drug Evaluation, Preclinical, High-Throughput Screening Assays, Humans, Phosphotransferases (Alcohol Group Acceptor), Protein Kinase Inhibitors, Small Molecule Libraries",
author = "Dominik Schr{\"o}der and Christoph Rehbach and Carola Seyffarth and Martin Neuenschwander and Kries, {Jens V} and Sabine Windhorst",
note = "Copyright {\textcopyright} 2013 Elsevier Inc. All rights reserved.",
year = "2013",
month = sep,
day = "20",
doi = "10.1016/j.bbrc.2013.08.053",
language = "English",
volume = "439",
pages = "228--34",
journal = "BIOCHEM BIOPH RES CO",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "2",

}

RIS

TY - JOUR

T1 - Identification of a new membrane-permeable inhibitor against inositol-1,4,5-trisphosphate-3-kinase A

AU - Schröder, Dominik

AU - Rehbach, Christoph

AU - Seyffarth, Carola

AU - Neuenschwander, Martin

AU - Kries, Jens V

AU - Windhorst, Sabine

N1 - Copyright © 2013 Elsevier Inc. All rights reserved.

PY - 2013/9/20

Y1 - 2013/9/20

N2 - Ectopic expression of the neuron-specific inositol-1,4,5-trisphosphate-3-kinase A (ITPKA) in lung cancer cells increases their metastatic potential because the protein exhibits two actin regulating activities; it bundles actin filaments and regulates inositol-1,4,5-trisphosphate (InsP3)-mediated calcium signals by phosphorylating InsP3. Thus, in order to inhibit the metastasis-promoting activity of ITPKA, both its actin bundling and its InsP3kinase activity has to be blocked. In this study, we performed a high throughput screen in order to identify specific and membrane-permeable substances against the InsP3kinase activity. Among 341,44 small molecules, 237 compounds (0.7%) were identified as potential InsP3kinase inhibitors. After determination of IC50-values, the three compounds with highest specificity and highest hydrophobicity (EPPC-3, BAMB-4, MEPTT-3) were further characterized. Only BAMB-4 was nearly completely taken up by H1299 cells and remained stable after cellular uptake, thus exhibiting a robust stability and a high membrane permeability. Determination of the inhibitor type revealed that BAMB-4 belongs to the group of mixed type inhibitors. Taken together, for the first time we identified a highly membrane-permeable inhibitor against the InsP3kinase activity of ITPKA providing the possibility to partly inhibit the metastasis-promoting effect of ITPKA in lung tumor cells.

AB - Ectopic expression of the neuron-specific inositol-1,4,5-trisphosphate-3-kinase A (ITPKA) in lung cancer cells increases their metastatic potential because the protein exhibits two actin regulating activities; it bundles actin filaments and regulates inositol-1,4,5-trisphosphate (InsP3)-mediated calcium signals by phosphorylating InsP3. Thus, in order to inhibit the metastasis-promoting activity of ITPKA, both its actin bundling and its InsP3kinase activity has to be blocked. In this study, we performed a high throughput screen in order to identify specific and membrane-permeable substances against the InsP3kinase activity. Among 341,44 small molecules, 237 compounds (0.7%) were identified as potential InsP3kinase inhibitors. After determination of IC50-values, the three compounds with highest specificity and highest hydrophobicity (EPPC-3, BAMB-4, MEPTT-3) were further characterized. Only BAMB-4 was nearly completely taken up by H1299 cells and remained stable after cellular uptake, thus exhibiting a robust stability and a high membrane permeability. Determination of the inhibitor type revealed that BAMB-4 belongs to the group of mixed type inhibitors. Taken together, for the first time we identified a highly membrane-permeable inhibitor against the InsP3kinase activity of ITPKA providing the possibility to partly inhibit the metastasis-promoting effect of ITPKA in lung tumor cells.

KW - Cell Line, Tumor

KW - Cell Membrane Permeability

KW - Drug Evaluation, Preclinical

KW - High-Throughput Screening Assays

KW - Humans

KW - Phosphotransferases (Alcohol Group Acceptor)

KW - Protein Kinase Inhibitors

KW - Small Molecule Libraries

U2 - 10.1016/j.bbrc.2013.08.053

DO - 10.1016/j.bbrc.2013.08.053

M3 - SCORING: Journal article

C2 - 23981806

VL - 439

SP - 228

EP - 234

JO - BIOCHEM BIOPH RES CO

JF - BIOCHEM BIOPH RES CO

SN - 0006-291X

IS - 2

ER -