Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/90866
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Type: Journal article
Title: A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties
Author: Pitman, M.
Powell, J.
Coolen, C.
Moretti, P.
Zebol, J.
Pham, D.
Finnie, J.
Don, A.
Ebert, L.
Bonder, C.
Gliddon, B.
Pitson, S.
Citation: Oncotarget, 2015; 6(9):7065-7083
Publisher: Impact Journals
Issue Date: 2015
ISSN: 1949-2553
1949-2553
Statement of
Responsibility: 
Melissa R. Pitman, Jason A. Powell, Carl Coolen, Paul A.B. Moretti, Julia R. Zebol, Duyen H. Pham, John W. Finnie, Anthony S. Don, Lisa M. Ebert, Claudine S. Bonder, Briony L. Gliddon, Stuart M. Pitson
Abstract: 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.
Keywords: apoptosis; in silico docking; molecular modeling; small molecule inhibitor; sphingosine kinase
Rights: All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License. PII: 3178
RMID: 0030026677
DOI: 10.18632/oncotarget.3178
Grant ID: http://purl.org/au-research/grants/nhmrc/1042589
http://purl.org/au-research/grants/nhmrc/1004695
Appears in Collections:Medicine publications

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