Synthesis and evaluation of sphingoid analogs as inhibitors of sphingosine kinases.
Sphingosine 1-phosphate (S1P), a product of sphingosine kinases (SphK), mediates diverse biological processes such as cell differentiation, proliferation, motility, and apoptosis. In an effort to search and identify specific inhibitors of human SphK, the inhibitory effects of synthetic sphingoid analogs on kinase activity were examined. Among the analogs tested, we found two, SG12 and SG14, that have specific inhibitory effects on hSphK2. N,N-Dimethylsphingosine (DMS), a well-known SphK inhibitor, displayed inhibitory effects for both SphK1 and SphK2, as well as protein kinase C. In contrast, SG12 and SG14 exhibited selective inhibitory effects on hSphK2. Furthermore, SG14 did not affect PKC. In isolated platelets, SG14 blocked the conversion of sphingosine into sphingosine 1-phosphate significantly. This is the first report on the identification of a hSphK2-specific inhibitor, which may provide a useful tool for studying the biological functions of hSphK2.
Kim
Jin-Wook
JW
Doosan Biotech, 39-3, Seongbok-dong, Yongin-si, Gyeonggi-do 449-795, Korea.
Kim
Yong-Woo
YW
Inagaki
Yuichi
Y
Hwang
You-A
YA
Mitsutake
Susumu
S
Ryu
Yeon-Woo
YW
Lee
Won Koo
WK
Ha
Hyun-Joon
HJ
Park
Chang-Seo
CS
Igarashi
Yasuyuki
Y
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D016466:CHO Cells / Q000187:drug effects / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005069:Evaluation Studies as Topic; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D000099157:Sphingosine Kinase
D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011493:Protein Kinase C; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate