| Vasculartargetingagentsforthetreatmentofcancersaredesignedtocausearapidandselectiveshutdownofthebloodvesselsandtumors.Ourpreviousstudyindicatedaserialdiarylisoxazolederivatives(TYCcompounds)relatedtoCA-4composedstronganti-cancerandanti-angiogenesisactivity.Utilizingproteinmodelingsimulationanalysis,TYCcompoundswerefoundtobedockedintoPim-1activesiteandspatiallyoverlappedwitheachother.Pim-1isanoncogene-encodedserine/threoninekinasewhichisassociatedwithmultiplecellularfunctionssuchasproliferation,survival,differentiation,apoptosis,andtumorigenesis.AmongtheseTYCcompounds,TYC84showedhighestconsensusscoringascomparedwithothers.Fourteenpositionswerefoundwithinthebindingsite.In3DstructureofPim-1,TYC84dockedintotheactivesiteofPim-1inthesamepocketasLY294002,aPI3kinaseinhibitor,resultedininhibitionofPim-1kinaseactivity.ThestructureofTYC84formshydrogen-bondswithSer-46andestablishes3non-polarcontactswithresiduesGly-45,Ile-104,andIle-185.AssociationofPim-1andMDM2hasbeenreportedtoinducetumorigenesis.Therefore,immunoblottingassaywasusedandconfirmedtheeffectofTYCcompoundsonreductionofPim-1andMDM2proteinexpression.Theoutcomeoftheseresultsshouldleadtoprovideinformationtodesignchemicalmodificationestimationofnovelandimprovedcompoundsforanticancertherapy. |