Design of Sphingosine Kinases Inhibitors: Challenges and Recent Developments

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 disease...

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Published inCurrent pharmaceutical design Vol. 25; no. 9; p. 956
Main Authors Magli, Elisa, Corvino, Angela, Fiorino, Ferdinando, Frecentese, Francesco, Perissutti, Elisa, Saccone, Irene, Santagada, Vincenzo, Caliendo, Giuseppe, Severino, Beatrice
Format Journal Article
LanguageEnglish
Published United Arab Emirates 01.01.2019
Subjects
Animals
Drug Design
Enzyme Inhibitors - chemistry
Humans
Lysophospholipids
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors
Protein Isoforms
Sphingosine - analogs & derivatives
Sphingosine Kinase 1
dual inhibitors
Sphingosine-1-phosphate
design
Sphingosine Kinase 2
selective inhibitors
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Summary: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. 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 profile. 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. 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.
ISSN:1873-4286
DOI:10.2174/1381612825666190404115424