Abstract
The sphingosine-1-phosphate (S1P) signaling pathway is an attractive drug target due to its involvement in immune cell chemotaxis and vascular integrity. The formation of S1P is catalyzed by sphingosine kinase 1 or 2 (SphK1 or SphK2) from sphingosine (Sph) and ATP. Inhibition of SphK1 and SphK2 to attenuate levels of S1P has been reported to be efficacious in animal models of diseases such as cancer, sickle cell disease, and renal fibrosis. While inhibitors of both SphKs have been reported, improvements in potency and selectivity are still needed. Toward that end, we performed structure-activity relationship profiling of 8 (SLM6031434) and discovered a heretofore unrecognized side cavity that increased inhibitor potency toward SphK2. Interrogating this region revealed that relatively small hydrophobic moieties are preferred, with 10 being the most potent SphK2-selective inhibitor (Ki = 89 nM, 73-fold SphK2-selective) with validated in vivo activity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amidines / chemical synthesis
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Amidines / chemistry
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Amidines / pharmacology*
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Animals
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Binding Sites
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Drug Discovery
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Humans
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Mice, Inbred C57BL
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Molecular Docking Simulation
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Molecular Structure
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Oxadiazoles / chemical synthesis
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Oxadiazoles / chemistry
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Oxadiazoles / pharmacology*
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Pyrrolidines / chemical synthesis
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacology*
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Saccharomyces cerevisiae
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Structure-Activity Relationship
Substances
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Amidines
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Oxadiazoles
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Protein Kinase Inhibitors
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Pyrrolidines
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SphK2-selective inhibitor 10
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase 2, human