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Beschreibung

A cell-permeable hydroxymethylpyrrolidine compound that inhibits sphingosine kinase-1/SphK1-catalyzed Sphingosine phosphorylation (IC50 = 2.0 nM, [sphingosine] = 3 µ,M) in a reversible and sphingosine-competitive manner (Ki = 3.6 nM), exhibiting no affinity toward S1P receptors and much reduced inhibitory activity against Sphk2 (6.8% inhibition at 10 µ,M) or 46 other lipid and portein kinases (IC50 >10 µ,M). Effectively depletes cellular S1P (by 90% with 1 h 200 nM or 7 d 1 µ,M drug exposure in 1483 cultures) with concomitant elevation of sphingosine level and no detectable cytotoxicity., A cell-permeable hydroxymethylpyrrolidine compound that acts as a high affinity (Kd = 5 nM, kofft1/2 = 8.5 min), but poor, sphingosine kinase-1/SphK1 substrate (1/1,500 of sphingosine processivity) and potently inhibits against SphK1-catalyzed sphingosine-to-S1P conversion (IC50 = 2.0 nM, [sphingosine] = 3 µ,M) in a reversible, sphingosine-, but not ATP-, competitive manner (Ki = 3.6 nM), exhibiting 132-fold selectivity over SphK2, no affinity toward S1P receptors (S1P1, S1P2, S1P3, S1P5), and much reduced or no inhibitory activity against a panel of 46 other lipid and protein kinases (IC50 >10 µ,M), including the structurally related diacylglyerol kinase alpha/DAGKalpha (3.7% inhibition at 10 µ,M). PF-543 exposure in 1483 squamous cultures is reported to result in intracellular S1P depletion (by 90% upon 1 h 200 nM or 7 d 1 µ,M drug exposure) with concomitant elevation of sphingosine level and no detectable cytotoxicity (1 µ,M for 7 to 9 d in 1483, A549, Jurkat, LN229, MCF7, or U937 cultures). Also active in human whole blood assays in the presence human & bovine serum proteins (IC50 = 26.7 nM against cellular C17-S1P formation from exogenously added 20 µ,M C17-sphingosine in 10 min with 30 min drug preincubation).