Development of amidine-based sphingosine kinase 1 nanomolar inhibitors and reduction of sphingosine 1-phosphate in human leukemia cells

Andrew J. Kennedy, Thomas P. Mathews, Yugesh Kharel, Saundra D. Field, Morgan L. Moyer, James E. East, Joseph D. Houck, Kevin R. Lynch, Timothy L. MacDonald

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Sphingosine 1-phosphate (S1P) is a bioactive lipid that has been identified as an accelerant of cancer progression. The sphingosine kinases (SphKs) are the sole producers of S1P, and thus, SphK inhibitors may prove effective in cancer mitigation and chemosensitization. Of the two SphKs, SphK1 overexpression has been observed in a myriad of cancer cell lines and tissues and has been recognized as the presumptive target over that of the poorly characterized SphK2. Herein, we present the design and synthesis of amidine-based nanomolar SphK1 subtype-selective inhibitors. A homology model of SphK1, trained with this library of amidine inhibitors, was then used to predict the activity of additional, more potent, inhibitors. Lastly, select amidine inhibitors were validated in human leukemia U937 cells, where they significantly reduced endogenous S1P levels at nanomolar concentrations.

Original languageEnglish (US)
Pages (from-to)3524-3548
Number of pages25
JournalJournal of Medicinal Chemistry
Volume54
Issue number10
DOIs
StatePublished - May 26 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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