Limits...
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.

Show MeSH

Related in: MedlinePlus

Sphingosine’smetabolic fates.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4301069&req=5

fig1: Sphingosine’smetabolic fates.

Mentions: FTY720is a prodrug; its first metabolite, phospho-FTY720 (formedby sphingosine kinase (SphK)), is an S1P analogue that is an agonistat the S1P1, 3, 4, and 5 receptors.4,5 Subsequentstudies with FTY720 analogues and genetically modified mice revealedthat agonists of the S1P1 receptor drive lymphopenia and, in primates,bradycardia, thus implicating endogenous S1P in control of lymphocytetrafficking and heart rate.6 The insightsgained through the study of FTY720, and its clinical success, haveencouraged investigations to validate additional S1P signaling pathwaymembers as drug targets, including individual S1P receptors, S1P lyase(cleaves S1P to hexadecenal and phospho-ethanolamine), and the S1Psynthetic enzyme, SphK (Figure 1). Our goalwith this review is to describe the current state of affairs regardingsphingosine kinase as a potential drug target, as revealed by chemicalbiology tools that are sphingosine kinase inhibitors.


Drugging sphingosine kinases.

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

Sphingosine’smetabolic fates.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Sphingosine’smetabolic fates.
Mentions: FTY720is a prodrug; its first metabolite, phospho-FTY720 (formedby sphingosine kinase (SphK)), is an S1P analogue that is an agonistat the S1P1, 3, 4, and 5 receptors.4,5 Subsequentstudies with FTY720 analogues and genetically modified mice revealedthat agonists of the S1P1 receptor drive lymphopenia and, in primates,bradycardia, thus implicating endogenous S1P in control of lymphocytetrafficking and heart rate.6 The insightsgained through the study of FTY720, and its clinical success, haveencouraged investigations to validate additional S1P signaling pathwaymembers as drug targets, including individual S1P receptors, S1P lyase(cleaves S1P to hexadecenal and phospho-ethanolamine), and the S1Psynthetic enzyme, SphK (Figure 1). Our goalwith this review is to describe the current state of affairs regardingsphingosine kinase as a potential drug target, as revealed by chemicalbiology tools that are sphingosine kinase inhibitors.

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