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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.

SUBMITTER: Raje MR

PROVIDER: S-EPMC3748591 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors.

Raje Mithun R MR Knott Kenneth K Kharel Yugesh Y Bissel Philippe P Lynch Kevin R KR Santos Webster L WL

Bioorganic & medicinal chemistry 20111115 1

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. ...[more]

PMID: 22137932

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