title: Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors.
abstract: Sphingosine kinase (SphK) has emerged as an attractive target for cancer therapeutics due to its role in cell survival. SphK phosphorylates sphingosine to form sphingosine 1-phosphate (S1P), which has been implicated in cancer growth and survival. SphK exists as two different isotypes, namely SphK1 and SphK2, which play different roles inside the cell. In this report, we describe SphK inhibitors based on the immunomodulatory drug, FTY720, which is phosphorylated by SphK2 to generate a S1P mimic. Structural modification of FTY720 provided a template for synthesizing new inhibitors. A diversity-oriented synthesis generated a library of SphK inhibitors with a novel scaffold and headgroup. We have discovered subtype selective inhibitors with K(i)'s in the low micromolar range. This is the first report describing quaternary ammonium salts as SphK inhibitors.
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Mithun R
authors.initials: MR
authors.lastname: Raje
authors.forename: Kenneth
authors.initials: K
authors.lastname: Knott
authors.forename: Yugesh
authors.initials: Y
authors.lastname: Kharel
authors.forename: Philippe
authors.initials: P
authors.lastname: Bissel
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
authors.forename: Webster L
authors.initials: WL
authors.lastname: Santos
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007700:Kinetics; D008246:Lysophospholipids / Q000737:chemistry; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011409:Propylene Glycols / Q000737:chemistry; D013110:Sphingosine / Q000031:analogs & derivatives / Q000737:chemistry; D013329:Structure-Activity Relationship; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000068876:Fingolimod Hydrochloride; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate