Background: Sphingosine kinases (SphKs) catalyze the phosphorylation of sphingosine to form the
bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P). S1P is an important lipid mediator with a wide
range of biological functions; it is also involved in a variety of diseases such as inflammatory diseases, Alzheimer’s
disease and cancer.
Methods: This review reports the recent advancement in the research of SphKs inhibitors. Our purpose is also to
provide a complete overview useful for underlining the features needed to select a specific pharmacological
Discussion: Two distinct mammalian SphK isoforms have been identified, SphK1 and SphK2. These isoforms
are encoded by different genes and exhibit distinct subcellular localizations, biochemical properties and functions.
SphK1 and SphK2 inhibition can be useful in different pathological conditions.
Conclusion: SphK1 and SphK2 have many common features but different and even opposite biological functions.
For this reason, several research groups are interested in understanding the therapeutic usefulness of a selective
or non-selective inhibitor of SphKs. Moreover, a compensatory mechanism for the two isoforms has been
demonstrated, thus leading to the development of dual inhibitors.