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

作者：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^*

来源：Oncotarget, 2015, 6(9): 7065-7083.

DOI：10.18632/oncotarget.3178

• Apoptosis
• in silico docking
• molecular modeling
• small molecule inhibitor
• sphingosine kinase

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 proproliferative 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.

• 出版日期2015-3-30