Development of a sphingosine kinase 1 specific small-molecule inhibitor.
The sphingolipid metabolic pathway represents a potential source of new therapeutic targets for numerous hyperproliferative/inflammatory diseases. Targets such as the sphingosine kinases (SphKs) have been extensively studied and numerous strategies have been employed to develop inhibitors against these enzymes. Herein, we report on the optimization of our novel small-molecule inhibitor SKI-I (N'-[(2-hydroxy-1-naphthyl)methylene]-3-(2-naphthyl)-1H-pyrazole-5-carbohydrazide) and the identification of a SphK1-specific analog, SKI-178, that is active in vitro and in vivo. This SphK1 specific small-molecule, non-lipid like, inhibitor will be of use to elucidate the roles of SphK1 and SphK2 in the development/progression of hyperproliferative and/or inflammatory diseases.
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033-0850, USA.
Jeremy A
JA
Hengst
Xujun
X
Wang
Ugir H
UH
Sk
Arun K
AK
Sharma
Shantu
S
Amin
Jong K
JK
Yun
D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D007700:Kinetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship; D000099157:Sphingosine Kinase
D004791:Enzyme Inhibitors; D006834:Hydrazines; D017853:Phosphotransferases (Alcohol Group Acceptor); D011720:Pyrazoles; D000099157:Sphingosine Kinase; C556358:N'-((1E)-1-(3,4-dimethoxyphenyl)ethylidene)-3-(4-methoxyphenyl)-1H-pyrazole-5-carbohydrazide; C556356:N'-((2-hydroxy-1-naphthyl)methylene)-3-(2-naphthyl)-1H-pyrazole-5-carbohydrazide