Oncotarget

Research Papers:

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

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 and Stuart M. Pitson _

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Oncotarget. 2015; 6:7065-7083. https://doi.org/10.18632/oncotarget.3178

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Abstract

Melissa R. Pitman1, Jason A. Powell1,3, Carl Coolen1, Paul A.B. Moretti1, Julia R. Zebol1, Duyen H. Pham1, John W. Finnie4,5, Anthony S. Don6, Lisa M. Ebert1,3, Claudine S. Bonder1,2,3, Briony L. Gliddon1, Stuart M. Pitson1,2,3,*

1Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia

2School of Molecular and Biomedical Science, University of Adelaide, SA 5005, Australia

3School of Medicine, University of Adelaide, SA 5005, Australia

4School of Veterinary Science, University of Adelaide, SA 5005, Australia

5SA Pathology, Hanson Institute Centre for Neurological Diseases, Adelaide, SA 5000, Australia

6Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia

Correspondence to:

Stuart M. Pitson, e-mail: stuart.pitson@unisa.edu.au

Keywords: Apoptosis, in silico docking, molecular modeling, small molecule inhibitor, sphingosine kinase

Received: September 05, 2014     Accepted: January 25, 2015     Published: March 11, 2015

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.


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