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Review
. 2015 Jan 16;10(1):225-33.
doi: 10.1021/cb5008426. Epub 2014 Nov 19.

Drugging sphingosine kinases

Webster L Santos  1 , Kevin R Lynch
Affiliations
Review

Drugging sphingosine kinases

Webster L Santos et al. ACS Chem Biol. .

Abstract

The transfer of the gamma phosphate from ATP to sphingosine (Sph) to generate a small signaling molecule, sphingosine 1-phosphate (S1P), is catalyzed by sphingosine kinases (SphK), which exist as two isoforms, SphK1 and SphK2. SphK is a key regulator of S1P and the S1P:Sph/ceramide ratio. Increases in S1P levels have been linked to diseases including sickle cell disease, cancer, and fibrosis. Therefore, SphKs are potential targets for drug discovery. However, the current chemical biology toolkit needed to validate these enzymes as drug targets is inadequate. With this review, we survey in vivo active SphK inhibitors and highlight the need for developing more potent and selective inhibitors.

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Figures

Figure 1
Figure 1
Sphingosine’s metabolic fates.
Figure 2
Figure 2
Intracellular S1P signaling affects transcription and mitochondrial integrity to induce apoptosis, which is distinct from inside–out signaling via S1P receptors.
Figure 3
Figure 3
First-generation sphingosine kinase inhibitors.
Figure 4
Figure 4
Interactions of SKI-II with SphK1. Reprinted with permission from ref (12). Copyright 2013 Cell Press.
Figure 5
Figure 5
Second-generation sphingosine kinase inhibitors.
Figure 6
Figure 6
Hydrogen-bond interaction of Amgen 82 with amino acid residues of SphK1. Reprinted with permission from ref (63). Copyright 2013 Elsevier.
See this image and copyright information in PMC

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