title: A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties.
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.
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia.
authors: Melissa R
authors: MR
authors: Pitman
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia.|School of Medicine, University of Adelaide, SA 5005, Australia.
authors: Jason A
authors: JA
authors: Powell
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia.
authors: Carl
authors: C
authors: Coolen
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia.
authors: Paul A B
authors: PA
authors: Moretti
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia.
authors: Julia R
authors: JR
authors: Zebol
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia.
authors: Duyen H
authors: DH
authors: Pham
authors: School of Veterinary Science, University of Adelaide, SA 5005, Australia.|SA Pathology, Hanson Institute Centre for Neurological Diseases, Adelaide, SA 5000, Australia.
authors: John W
authors: JW
authors: Finnie
authors: Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors: Anthony S
authors: AS
authors: Don
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia.|School of Medicine, University of Adelaide, SA 5005, Australia.
authors: Lisa M
authors: LM
authors: Ebert
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia.|School of Molecular and Biomedical Science, University of Adelaide, SA 5005, Australia.|School of Medicine, University of Adelaide, SA 5005, Australia.
authors: Claudine S
authors: CS
authors: Bonder
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia.
authors: Briony L
authors: BL
authors: Gliddon
authors: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia.|School of Molecular and Biomedical Science, University of Adelaide, SA 5005, Australia.|School of Medicine, University of Adelaide, SA 5005, Australia.
authors: Stuart M
authors: SM
authors: Pitson
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008968:Molecular Conformation; D016296:Mutagenesis; D009154:Mutation; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013107:Sphingolipids / Q000737:chemistry; D000099157:Sphingosine Kinase
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D013107:Sphingolipids; D000099157:Sphingosine Kinase
keywords: apoptosis; in silico docking; molecular modeling; small molecule inhibitor; sphingosine kinase