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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Design of Sphingosine Kinases Inhibitors: Challenges and Recent Developments

Author(s): Elisa Magli, Angela Corvino, Ferdinando Fiorino, Francesco Frecentese, Elisa Perissutti, Irene Saccone, Vincenzo Santagada, Giuseppe Caliendo* and Beatrice Severino

Volume 25, Issue 9, 2019

Page: [956 - 968] Pages: 13

DOI: 10.2174/1381612825666190404115424

Price: $65


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 profile.

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.

Keywords: Sphingosine-1-phosphate, Sphingosine Kinase 1, Sphingosine Kinase 2, design, dual inhibitors, selective inhibitors.

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