Lenalidomide-hydrochloride-CC-5013-hydrochloride-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemELenalidomidehydrochlorideCat.No.:HY-A0003ACASNo.:1243329-97-6Synonyms:CC-5013hydrochloride分⼦式:C₁₃H₁₄ClN₃O₃分⼦量:295.72作⽤靶点:LigandsforE3Ligase;MolecularGlues作⽤通路:PROTAC储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性Lenalidomidehydrochloride(CC-5013hydrochloride)Thalidomide的衍⽣物，也⼀种具有⼝服活性免疫调节剂，以分⼦胶的⽅式作⽤。Lenalidomidehydrochloride(CC-5013hydrochloride)⼀种泛素E3连接酶cereblon(CRBN)的配体，通过CRBN-CRL4泛素连接酶对两种淋巴转录因⼦IKZF1和IKZF3进⾏选择性泛素化和降解。Lenalidomidehydrochloride(CC-5013hydrochloride)特别地抑制成熟B细胞淋巴瘤(包括多发性⾻髓瘤)的⽣长，并诱导T细胞释放⽩细胞介素-2(IL-2)[1][2]。IC50&TargetCereblon体外研究LenalidomideispotentinstimulatingTcellproliferationandIFN-γandIL-2production.LenalidomidehasbeenshowntoinhibitproductionofproinflammatorycytokinesTNF-α,IL-1,IL-6,IL-12andelevatetheproductionofanti-inflammatorycytokineIL-10fromhumanPBMCs.LenalidomidedownregulatestheproductionofIL-6directlyandalsobyinhibitingmultiplemyeloma(MM)cellsandbonemarrowstromalcells(BMSC)interaction,whichaugmentstheapoptosisofmyelomacells[2].Dose-dependentinteractionwiththeCRBN-DDB1complexisobservedwithThalidomide,LenalidomideandPomalidomide,withIC50valuesof~30ꢀμM,~3ꢀμMand~3ꢀμM,respectively,ThesereducedCRBNexpressioncells(U266-CRBN60andU266-CRBN75)arelessresponsivethantheparentalcellstoantiproliferativeeffectsLenalidomideacrossadose-responserangeof0.01to10ꢀμM[3].Lenalidomide,athalidomideanalog,functionsasamoleculargluebetweenthehumanE3ubiquitinligasecereblonandCKIαisshowntoinducetheubiquitinationanddegradationofthiskinase,thuspresumablykillingleukemiccellsbyp53activation[5].体内研究ThetoxicityofLenalidomidedosesupto15,22.5,and45mg/kgviaIV,IP,andPOroutesofadministration.1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemELimitedbysolubilityinourPBSdosingvehicle,thesemaximumachievableLenalidomidedosesarewelltoleratedwiththeexceptionofonemousedeath(offourtotaldosed)atthe15mg/kgIVdose.Notably,noothertoxicitiesareobservedinthestudyatIVdosesof15mg/kg(n=3)or10mg/kg(n=45)oratanyotherdoselevelthroughIV,IP,andPOroutes[4].PROTOCOLCellAssay[3]CelllinesNCI-H929andU266,andDF15cellsaregrowninRPMI-I640mediumcontaining10%(V/V)heat-inactivatedfetalbovineserumsupplementedwith2ꢀmMglutamine.ToproduceLenalidomideresistantcelllines,NCI-H929cellsaretreatedcontinuously(freshLenalidomideisaddedevery3-4days)withcontrol(final0.1%DMSO)orlow-doseLenalidomide(1ꢀμM)for2monthsuntiltheproliferationofcellsisnolongerinhibitedbyLenalidomide(1ꢀμM),asdeterminedbycellviability(Vi-cellXRcellviabilityanalyzer),cellproliferationbyflowcytometryandcellcycleanalysis(propidiumiodidestaining).Afteracquisitionofresistanceto1ꢀμM,theresistantH929celllinesaretreatedwithLenalidomide(10ꢀμM)forafurther4months.Afterthisperiodoftime,thecellculturesachievedfullyestablishresistanceuptohigh-doseLenalidomide(30ꢀμM).Priortotheexperimentsdescribedhere,H929Lenalidomide-resistantcellsaretakenoutofculturewithcompoundsfor5-7daysbeforeuse[3].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalMice[4]Administration[4]Imprintingcontrolregion(ICR)mice8-10weeksofageareused.Lenalidomideisincompletelysolubleat3.5mg/mLandaboveinPBScontaining1%HCl,asvisibleparticulatesremainedafterthoroughmixing.Therefore3mg/mLisselectedasthemaximumdosingsolutionconcentration(withnovisibleparticulates).Single,individualmiceareinitiallydosedwith3,10,or15mg/kgIV;4.5,15,or22.5mg/kgIP;and9,30,or45mg/kgPO.Additionalmice(n=4)arethenevaluatedatthemaximumdoseachievablebyvolumeandsolubilityofLenalidomideinthedosingsolution.Allmicearemonitoredcloselyfor1handre-evaluatedfortoxicities3,6,and24hpostdose.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.户使⽤本产品发表的科研⽂献•Cell.2018Sep20;175(1):171-185.e25.•CancerCell.2022Aug26;S1535-6108(22)00372-5.•NatCancer.2022May;3(5):595-613.•NatCommun.2017May22;8:15398.•NatChemBiol.2021Jun;17(6):711-717.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].OmranA,etal.EffectsofMRP8,LPS,andlenalidomideontheexpressionsofTNF-α,brain-enriched,andinflammation-related2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEmicroRNAsintheprimaryastrocyteculture.ScientificWorldJournal.2013Sep21;2013:208309.[2].KotlaV,etal.Mechanismofactionoflenalidomideinhematologicalmalignancies.JHematolOncol.2009Aug12;2:36.[3].Lopez-GironaA,etal.Cereblonisadirectproteintargetforimmunomodulatoryandantiproliferativeactivitiesoflenalidomideandpomalidomide.Leukemia.2012Nov;26(11):2326-35.[4].RozewskiDM,etal.Pharmacokineticsandtissuedispositionoflenalidomideinmice.AAPSJ.2012Dec;14(4):872-82.[5].MinzelW,etal.SmallMoleculesCo-targetingCKIαandtheTranscriptionalKinasesCDK7/9ControlAMLinPreclinicalModels.Cell.2018Sep20;175(1):171-185.e25.[6].KrönkeJ,etal.Lenalidomideinducesdegr