Importance of sphingosine kinase (SphK) as a target in developing cancer therapeutics and recent developments in the synthesis of novel SphK inhibitors.
Sphingosine kinase (SphK) is an oncogenic lipid kinase that regulates the sphingolipid metabolic pathway that has been shown to play a role in numerous hyperproliferative/inflammatory diseases. The SphK isoforms (SphK1 and SphK2) catalyze the conversion of the proapoptotic substrate d-erythrosphingosine to the promitogenic/migratory product sphingosine 1-phosphate (S1P). Accumulation of S1P has been linked to the development/progression of cancer and various other diseases including, but not limited to, asthma, inflammatory bowel disease, rheumatoid arthritis, and diabetic nephropathy. SphK therefore represents a potential new target for developing novel therapeutics for cancer and other diseases. This finding has stimulated the development and evaluation of numerous SphK inhibitors over the past decade or so. In this review, we highlight the recent advancement in the field of SphK inhibitors including SphK1 and SphK2 specific inhibitors. Both sphingolipid based and nolipidic small molecule inhibitors and their importance in treatment of cancer and other diseases are discussed.
Department of Pharmacology, Penn State Hershey Cancer Institute, CH72, Penn State College of Medicine , 500 University Drive, Hershey, Pennsylvania 17033, United States.
Daniel
D
Plano
Shantu
S
Amin
Arun K
AK
Sharma
D002994:Clofibrate / Q000378:metabolism; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008246:Lysophospholipids / Q000819:agonists / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011217:Practolol / Q000378:metabolism; D013110:Sphingosine / Q000819:agonists / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000099157:Sphingosine Kinase
D002994:Clofibrate; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011217:Practolol; D013110:Sphingosine; D000099157:Sphingosine Kinase; C010138:eramide; C481931:erythro-(2R,3S)-sphingosine; C060506:sphingosine 1-phosphate