Doramapimod-BIRB-796-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEDoramapimodCat.No.:HY-10320CASNo.:285983-48-4Synonyms:BIRB796分?式:C??H??N?O?分?量:527.66作?靶點:p38MAPK;Raf;Autophagy作?通路:MAPK/ERKPathway;Autophagy儲存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數(shù)據(jù)體外實驗DMSO:125mg/mL(236.89mM;Needultrasonic)Ethanol:33.33mg/mL(63.17mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲備液1mM1.8952mL9.4758mL18.9516mL5mM0.3790mL1.8952mL3.7903mL10mM0.1895mL0.9476mL1.8952mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；?旦配成溶液，請分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲存時，請在6個?內(nèi)使?，-20°C儲存時，請在1個?內(nèi)使?。體內(nèi)實驗請根據(jù)您的實驗動物和給藥?式選擇適當(dāng)?shù)娜芙?案。以下溶解?案都請先按照InVitro?式配制澄的儲備液，再依次添加助溶劑：(為保證實驗結(jié)果的可靠性，澄的儲備液可以根據(jù)儲存條件，適當(dāng)保存；體內(nèi)實驗的?作液，建議您現(xiàn)?現(xiàn)配，當(dāng)天使?；以下溶劑前顯?的百分?指該溶劑在您配制終溶液中的體積占?；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的?式助溶)1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE1.請依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥2.08mg/mL(3.94mM);Clearsolution2.請依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:2.08mg/mL(3.94mM);Suspendedsolution;Needultrasonic3.請依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(4.74mM);ClearsolutionBIOLOGICALACTIVITY?物活性Doramapimod(BIRB796)?種具有?服活性的，?效的p38MAPK抑制劑，IC50值分別為p38α=38nM，p38β=65nM，p38γ=200nM，p38δ=520nM。Doramapimod對p38激酶具有?爾親和?(Kd=0.1nM)。Doramapimod也抑制B-Raf和Abl，IC50分別為83nM和14.6μM[1][2]。IC50&Targetp38αp38βp38δp38γ38nM(IC50)65nM(IC50)520nM(IC50)200nM(IC50)B-RafAblp38MAPkinase83.4nM(IC50)14600nM(IC50)0.1nM(Kd)體外研究Doramapimod(BIRB796)isusuallyassociatedwithinflammationbecauseofitsroleinT-cellproliferationandcytokineproduction[1].Doramapimod(BIRB796)blocksthestress-inducedphosphorylationofthescaffoldproteinSAP97,furtherestablishingthatthisisaphysiologicalsubstrateofSAPK3/p38γ.ThebindingofDoramapimodtothep38MAPKsorJNK1/2isimpairingtheirphosphorylationbytheupstreamkinaseMKK6orMKK4[3].體內(nèi)研究ThemeanxenograftweighofDoramapimod(BIRB796)islighterthancontrol.TheinhibitionrateofDoramapimodis1.93%[4].TheDoramapimod(BIRB796)treatmentslightlyreducesbloodpressure(166±7mmHgatweek7;P[5].PROTOCOLCellAssay[3]Humanembryonickidney(HEK)293andHeLacellsareexposedto0.5Msorbitolfor30minor100ng/mLEGFfor10minandthenlysedinbufferA(50mMTris-HCl,pH7.5,1mMEGTA,1mMEDTA,1mMsodiumorthovanadate,10mMsodiumfluoride,50mMsodiumβ-glycerophosphate,5mMpyrophosphate,0.27Msucrose,0.1mMphenylmethylsulfonylfluoride,1%(v/v)TritonX-100)plus0.1%(v/v)2-mercaptoethanolandCompleteproteinaseinhibitormixture.Lysatesarecentrifugedat18,000×gfor5minat4°C,andthesupernatantsareremoved,quick-frozeninliquidnitrogen,andstoredat-20°Cuntiluse.Whenrequired,cellsarepreincubatedfor1hwithoutorwith10μMSB203580or10μMPD184352orwithdifferentconcentrationsofDoramapimodforthetimesindicatedinthefigures[3].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalMice[4]2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEAdministration[4][5]Athymicnudemice(BALB/c-nu/nu),6to8weeksofageandweighing18to24g,areused.ThemicearetreatedwithDoramapimod(10mg/kgp.o.,every3days×5).Thebodyweightsoftheanimalsandthetwoperpendiculartumordiameters(AandB)arerecordedevery3days,andthetumorvolume(V)isestimated.Rats[5]MaletransgenicdTGRs(RCCLtd)andage-matchednontransgenicSprague-Dawley(SD)rats(MDC)areuse.2differentprotocolsareperformed.Inprotocol2,untreateddTGR(n=15),dTGR+BIRB796(30mg/kgperdayinthedietfor3weeks;n=11),andSD(n=8eachgroup)ratsareanalyzed.Systolicbloodpressureismeasuredweeklybytailcuff.Twenty-four-hoururinesamplesarecollectedinmetaboliccagesfromweeks5to7.Serumiscollectedatweek7.SerumcreatinineandcystatinCaremeasuredbyclinicalroutineassays.Urinaryratalbuminisdeterminedbyenzyme-linkedimmunosorbentassay.Theaimofprotocol2istofocusonelectrophysiologicalalterationsandmortality.UntreateddTGR(n=10),dTGR+BIRB796(n=10),andSD(n=10)ratsarestudieduptoweek8.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.戶使?本產(chǎn)品發(fā)表的科研?獻?Nature.2019Jul;571(7763):127-131.?CellRes.2020Jul;30(7):574-589.?SciTranslMed.2018Jul18;10(450).pii:eaaq1093.?DevCell.2021Dec20;56(24):3334-3348.e6.?ExpMolMed.2021Sep21.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].DietrichJ,etal.Thedesign,synthesis,andevaluationof8hybridDFG-outallosterickinaseinhibitors.BioorgMedChem.2010Aug1;18(15):5738-48[2].CicenasJ,etal.JNK,p38,ERK,andSGK1InhibitorsinCancer.Cancers(Basel).2017Dec21;10(1).pii:E1.[3].KumaY,etal.BIRB796inhibitsallp38MAPKisoformsinvitroandinvivo.JBiolChem,2005,280(20),19472-19479.[4].HeD,etal.BIRB796,theinhibitorofp38mitogen-activatedproteinkinase,enhancestheefficacyofchemotherapeuticagentsinABCB1overexpressioncells.PLoSOne.2013;8(1):e54181.[5].ParkJK,etal.p38mitogen-activatedproteinkinaseinhibitionamelioratesangiotensinI