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A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties

The dynamic balance of cellular sphingolipids, the sphingolipid rheostat, is an important determinant of cell fate, and is commonly deregulated in cancer. Sphingosine 1-phosphate is a signaling molecule with anti-apoptotic, pro-proliferative and pro-angiogenic effects, while conversely, ceramide and...

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Autores principales: Pitman, Melissa R., Powell, Jason A., Coolen, Carl, Moretti, Paul A.B., Zebol, Julia R., Pham, Duyen H., Finnie, John W., Don, Anthony S., Ebert, Lisa M., Bonder, Claudine S., Gliddon, Briony L., Pitson, Stuart M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466670/
https://www.ncbi.nlm.nih.gov/pubmed/25788259
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author Pitman, Melissa R.
Powell, Jason A.
Coolen, Carl
Moretti, Paul A.B.
Zebol, Julia R.
Pham, Duyen H.
Finnie, John W.
Don, Anthony S.
Ebert, Lisa M.
Bonder, Claudine S.
Gliddon, Briony L.
Pitson, Stuart M.
author_facet Pitman, Melissa R.
Powell, Jason A.
Coolen, Carl
Moretti, Paul A.B.
Zebol, Julia R.
Pham, Duyen H.
Finnie, John W.
Don, Anthony S.
Ebert, Lisa M.
Bonder, Claudine S.
Gliddon, Briony L.
Pitson, Stuart M.
author_sort Pitman, Melissa R.
collection PubMed
description The dynamic balance of cellular sphingolipids, the sphingolipid rheostat, is an important determinant of cell fate, and is commonly deregulated in cancer. Sphingosine 1-phosphate is a signaling molecule with anti-apoptotic, pro-proliferative and pro-angiogenic effects, while conversely, ceramide and sphingosine are pro-apoptotic. The sphingosine kinases (SKs) are key regulators of this sphingolipid rheostat, and are attractive targets for anti-cancer therapy. Here we report a first-in-class ATP-binding site-directed small molecule SK inhibitor, MP-A08, discovered using an approach of structural homology modelling of the ATP-binding site of SK1 and in silico docking with small molecule libraries. MP-A08 is a highly selective ATP competitive SK inhibitor that targets both SK1 and SK2. MP-A08 blocks pro-proliferative signalling pathways, induces mitochondrial-associated apoptosis in a SK-dependent manner, and reduces the growth of human lung adenocarcinoma tumours in a mouse xenograft model by both inducing tumour cell apoptosis and inhibiting tumour angiogenesis. Thus, this selective ATP competitive SK inhibitor provides a promising candidate for potential development as an anti-cancer therapy, and also, due to its different mode of inhibition to other known SK inhibitors, both validates the SKs as targets for anti-cancer therapy, and represents an important experimental tool to study these enzymes.
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spelling pubmed-44666702015-06-22 A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties Pitman, Melissa R. Powell, Jason A. Coolen, Carl Moretti, Paul A.B. Zebol, Julia R. Pham, Duyen H. Finnie, John W. Don, Anthony S. Ebert, Lisa M. Bonder, Claudine S. Gliddon, Briony L. Pitson, Stuart M. Oncotarget Research Paper The dynamic balance of cellular sphingolipids, the sphingolipid rheostat, is an important determinant of cell fate, and is commonly deregulated in cancer. Sphingosine 1-phosphate is a signaling molecule with anti-apoptotic, pro-proliferative and pro-angiogenic effects, while conversely, ceramide and sphingosine are pro-apoptotic. The sphingosine kinases (SKs) are key regulators of this sphingolipid rheostat, and are attractive targets for anti-cancer therapy. Here we report a first-in-class ATP-binding site-directed small molecule SK inhibitor, MP-A08, discovered using an approach of structural homology modelling of the ATP-binding site of SK1 and in silico docking with small molecule libraries. MP-A08 is a highly selective ATP competitive SK inhibitor that targets both SK1 and SK2. MP-A08 blocks pro-proliferative signalling pathways, induces mitochondrial-associated apoptosis in a SK-dependent manner, and reduces the growth of human lung adenocarcinoma tumours in a mouse xenograft model by both inducing tumour cell apoptosis and inhibiting tumour angiogenesis. Thus, this selective ATP competitive SK inhibitor provides a promising candidate for potential development as an anti-cancer therapy, and also, due to its different mode of inhibition to other known SK inhibitors, both validates the SKs as targets for anti-cancer therapy, and represents an important experimental tool to study these enzymes. Impact Journals LLC 2015-03-11 /pmc/articles/PMC4466670/ /pubmed/25788259 Text en Copyright: © 2015 Pitman et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Pitman, Melissa R.
Powell, Jason A.
Coolen, Carl
Moretti, Paul A.B.
Zebol, Julia R.
Pham, Duyen H.
Finnie, John W.
Don, Anthony S.
Ebert, Lisa M.
Bonder, Claudine S.
Gliddon, Briony L.
Pitson, Stuart M.
A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties
title A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties
title_full A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties
title_fullStr A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties
title_full_unstemmed A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties
title_short A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties
title_sort selective atp-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466670/
https://www.ncbi.nlm.nih.gov/pubmed/25788259
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