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Drugging sphingosine kinases.

Santos WL, Lynch KR - ACS Chem. Biol. (2014)

Bottom Line: SphK is a key regulator of S1P and the S1P:Sph/ceramide ratio.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Virginia Tech , Blacksburg, Virginia 24061, United States.

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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First-generation sphingosine kinase inhibitors.
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fig3: First-generation sphingosine kinase inhibitors.

Mentions: The earliest SphK inhibitors were low-potency,not selective, andinadequately characterized (Figure 3). Thefirst inhibitors announced are simple analogues of Sph. Reductionof the double bond in Sph generated d,l-threo-dihydrosphingosine (DHS, safingol), which has an estimated Ki of ∼3–6 μM for SphK1.37 While DHS acts as a competitive inhibitor ofSph, it is a substrate for SphK2 and enters the sphingolipid metabolicpathway.7 Unfortunately, DHS is also aprotein kinase Cα inhibitor and has other off-target effects.38


Drugging sphingosine kinases.

Santos WL, Lynch KR - ACS Chem. Biol. (2014)

First-generation sphingosine kinase inhibitors.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4301069&req=5

fig3: First-generation sphingosine kinase inhibitors.
Mentions: The earliest SphK inhibitors were low-potency,not selective, andinadequately characterized (Figure 3). Thefirst inhibitors announced are simple analogues of Sph. Reductionof the double bond in Sph generated d,l-threo-dihydrosphingosine (DHS, safingol), which has an estimated Ki of ∼3–6 μM for SphK1.37 While DHS acts as a competitive inhibitor ofSph, it is a substrate for SphK2 and enters the sphingolipid metabolicpathway.7 Unfortunately, DHS is also aprotein kinase Cα inhibitor and has other off-target effects.38

Bottom Line: SphK is a key regulator of S1P and the S1P:Sph/ceramide ratio.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Virginia Tech , Blacksburg, Virginia 24061, United States.

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.

Show MeSH
Related in: MedlinePlus