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Biochem Biophys Res Commun. 2013 Sep 20;439(2):228-34. doi: 10.1016/j.bbrc.2013.08.053. Epub 2013 Aug 24.

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

Author information

1
Institut für Biochemie und Signaltransduktion, UKE Hamburg, Martinistr. 52, 20246 Hamburg, Germany.

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:

Cellular uptake; High-throughput screening; ITPKA; ITPKA-inhibitor; InsP(3); Metastasis; Mixed inhibition type

PMID:
23981806
DOI:
10.1016/j.bbrc.2013.08.053
[Indexed for MEDLINE]

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