PF-543isapotentinhibitorofsphingosinekinase1(SK1;IC50=2-3.6nM)thatlesseffectivelyinhibitsSK2(IC50=356nM).(1)Itdoesnotsignificantlyblocktheactivityofotherproteinandlipidkinases,orbindsphingosine-1-phosphatereceptors,whentestedataconcentrationof10µM.1PF-543preventsthephosphorylationofsphingosineincancercellsandinwholeblood(EC50=8.4and27nM,respectively).1ThroughitseffectsonSK1,PF-543preventssickling,hemolysis,andinflammationinsicklingcelldiseasetransgenicmice.(2)UnlikeinhibitorsthatareselectiveforSK2,PF-543doesnotimpairDNAsynthesisinhumanpulmonaryarterialsmoothmusclecells.(3) Storage-20CorbelowReferences:1)M.E.Schnute,M.D.McReynolds,T.Kasten,etal.“ModulationofcellularS1Plevelswithanovel,potentandspecificinhibitorofsphingosinekinase-1”BiochemistryJournal2012,444,79-88. 2)Y.Zhang,V.Berka,A.Song,etal.Elevatedsphingosine-1-phosphatepromotessicklingandsicklecelldiseaseprogression.J.Clin.Invest.2014,124,2750-2761. 3)H.S.Byun,S.Pyne,N.Macritchie,etal.Novelsphingosine-containinganaloguesselectivelyinhibitsphingosinekinase(SK)isozymes,induceSK1proteasomaldegradationandreduceDNAsynthesisinhumanpulmonaryarterialsmoothmusclecells.Med.Chem.Comm.2013,4,1-15. |