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

// Melissa R. Pitman 1 , Jason A. Powell 1, 3 , Carl Coolen 1 , Paul A.B. Moretti 1 , Julia R. Zebol 1 , Duyen H. Pham 1 , John W. Finnie 4, 5 , Anthony S. Don 6 , Lisa M. Ebert 1, 3 , Claudine S. Bonder 1, 2, 3 , Briony L. Gliddon 1 , Stuart M. Pitson 1, 2, 3, * 1 Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia 2 School of Molecular and Biomedical Science, University of Adelaide, SA 5005, Australia 3 School of Medicine, University of Adelaide, SA 5005, Australia 4 School of Veterinary Science, University of Adelaide, SA 5005, Australia 5 SA Pathology, Hanson Institute Centre for Neurological Diseases, Adelaide, SA 5000, Australia 6 Prince 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.