title: Sphingosine kinase inhibitors: a review of patent literature (2006-2015).
abstract: Sphingosine kinase (SphK1 & SphK2) is the sole source of the pleiotropic lipid mediator, sphingosine-1-phosphate (S1P). S1P has been implicated in a variety of diseases such as cancer, Alzheimer's disease, sickle cell disease and fibrosis and thus the biosynthetic route to S1P is a logical target for drug discovery. Areas covered: In this review, the authors consider the SphK inhibitor patent literature from 2006-2016 Q1 with the emphasis on composition of matter utility patents. The Espacenet database was queried with the search term 'sphingosine AND kinase' to identify relevant literature. Expert opinion: Early inhibitor discovery focused on SphK1 with a bias towards oncology indications. Structurally, the reported inhibitors occupy the sphingosine 'J-shaped' binding pocket. The lack of cytotoxicity with improved SphK1 inhibitors raises doubt about the enzyme as an oncology target. SphK2 inhibitors are featured in more recent patent applications. Interestingly, both SphK1 and SphK2 inhibition and gene 'knockout' share opposing effects on circulating S1P levels: SphK1 inhibition/gene ablation decreases, while SphK2 inhibition/gene ablation increases, blood S1P. As understanding of S1P's physiological roles increases and more drug-like SphK inhibitors emerge, inhibiting one or both SphK isotypes could provide unique strategies for treating disease.
authors.affiliation: a Department of Pharmacology , University of Virginia , Charlottesville , VA , USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
authors.affiliation: b SphynKx Therapeutics, LLC ., Charlottesville , VA , USA.
authors.forename: S Brandon
authors.initials: SB
authors.lastname: Thorpe
authors.affiliation: c Department of Chemistry and Virginia Tech Center for Drug Discovery , Virginia Tech , Blacksburg , VA , USA.
authors.forename: Webster L
authors.initials: WL
authors.lastname: Santos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010330:Patents as Topic; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase; C000594250:sphingosine kinase 2, human
keywords: Sphingosine kinase; cancer therapeutics; kinase inhibitor; sphingosine kinase 1; sphingosine kinase 2; sphingosine-1-phosphate