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

Hoe-Sup Byun, Susan Pyne, Neil Macritchie, Nigel J Pyne, Robert Bittman

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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-deoxysphinganines 55-21 and 77-7 are 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 inhibitors PF-543 and VPC96091 failed to inhibit DNA synthesis. These findings indicate that moderate potency inhibitors such as 55-21 are likely to have utility in unraveling the functions of SK1 in inflammatory and hyperproliferative disorders.

Original languageEnglish
Pages (from-to)1394-1399
Number of pages6
JournalMedChemComm
Volume4
Issue number10
Early online date6 Aug 2013
DOIs
Publication statusPublished - 1 Oct 2013

Keywords

  • pulmonary arterial hypertension
  • cancer
  • novel sphingosine kinase 1
  • smooth muscle cell

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