Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemELenalidomidehydrochlorideCat.No.:HY-A0003ACASNo.:1243329-97-6Synonyms:CC-5013hydrochloride分?式:C??H??ClN?O?分?量:295.72作?靶點(diǎn):LigandsforE3Ligase;MolecularGlues作?通路:PROTAC儲(chǔ)存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物活性Lenalidomidehydrochloride(CC-5013hydrochloride)Thalidomide的衍?物，也?種具有?服活性免疫調(diào)節(jié)劑，以分?膠的?式作?。Lenalidomidehydrochloride(CC-5013hydrochloride)?種泛素E3連接酶cereblon(CRBN)的配體，通過(guò)CRBN-CRL4泛素連接酶對(duì)兩種淋巴轉(zhuǎn)錄因?IKZF1和IKZF3進(jìn)?選擇性泛素化和降解。Lenalidomidehydrochloride(CC-5013hydrochloride)特別地抑制成熟B細(xì)胞淋巴瘤(包括多發(fā)性?髓瘤)的?長(zhǎng)，并誘導(dǎo)T細(xì)胞釋放?細(xì)胞介素-2(IL-2)[1][2]。IC50&TargetCereblon體外研究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~30?μM,~3?μMand~3?μM,respectively,ThesereducedCRBNexpressioncells(U266-CRBN60andU266-CRBN75)arelessresponsivethantheparentalcellstoantiproliferativeeffectsLenalidomideacrossadose-responserangeof0.01to10?μM[3].Lenalidomide,athalidomideanalog,functionsasamoleculargluebetweenthehumanE3ubiquitinligasecereblonandCKIαisshowntoinducetheubiquitinationanddegradationofthiskinase,thuspresumablykillingleukemiccellsbyp53activation[5].體內(nèi)研究ThetoxicityofLenalidomidedosesupto15,22.5,and45mg/kgviaIV,IP,andPOroutesofadministration.1/3MasterofBioactiveMolecules—您?邊的抑制劑?師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-inactivatedfetalbovineserumsupplementedwith2?mMglutamine.ToproduceLenalidomideresistantcelllines,NCI-H929cellsaretreatedcontinuously(freshLenalidomideisaddedevery3-4days)withcontrol(final0.1%DMSO)orlow-doseLenalidomide(1?μM)for2monthsuntiltheproliferationofcellsisnolongerinhibitedbyLenalidomide(1?μM),asdeterminedbycellviability(Vi-cellXRcellviabilityanalyzer),cellproliferationbyflowcytometryandcellcycleanalysis(propidiumiodidestaining).Afteracquisitionofresistanceto1?μM,theresistantH929celllinesaretreatedwithLenalidomide(10?μM)forafurther4months.Afterthisperiodoftime,thecellculturesachievedfullyestablishresistanceuptohigh-doseLenalidomide(30?μM).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.戶(hù)使?本產(chǎn)品發(fā)表的科研?獻(xiàn)?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?邊的抑制劑?師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].Kr?nkeJ,etal.Lenalidomideinducesdegr