title: Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells.
abstract: Sphingosine 1-phosphate (S1P) is involved in hyper-proliferative diseases such as cancer and pulmonary arterial hypertension. We have synthesized inhibitors that are selective for the two isoforms of sphingosine kinase (SK1 and SK2) that catalyze the synthesis of S1P. A thiourea adduct of sphinganine (F02) is selective for SK2 whereas the 1-deoxysphinganines55-21and77-7are selective for SK1. (2S,3R)-1-Deoxysphinganine (55-21) induced the proteasomal degradation of SK1 in human pulmonary arterial smooth muscle cells and inhibited DNA synthesis, while the more potent SK1 inhibitorsPF-543andVPC96091failed to inhibit DNA synthesis. These findings indicate that moderate potency inhibitors such as55-21are likely to have utility in unraveling the functions of SK1 in inflammatory and hyperproliferative disorders.
authors.affiliation: Department of Chemistry and Biochemistry, Queens College, The City University of New York, Flushing, NY 11367-1597, USA. Tel: +1 718-997-3279.
authors.forename: Hoe-Sup
authors.initials: HS
authors.lastname: Byun
authors.affiliation: Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
authors.affiliation: Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Macritchie
authors.affiliation: Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
authors.affiliation: Department of Chemistry and Biochemistry, Queens College, The City University of New York, Flushing, NY 11367-1597, USA. Tel: +1 718-997-3279.
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman