Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemELXH254Cat.No.:HY-112089CASNo.:1800398-38-2分?式:C??H??F?N?O?分?量:502.49作?靶點:Raf;p38MAPK;Bcr-Abl作?通路:MAPK/ERKPathway;ProteinTyrosineKinase/RTK儲存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數據體外實驗DMSO:100mg/mL(199.01mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲備液1mM1.9901mL9.9504mL19.9009mL5mM0.3980mL1.9901mL3.9802mL10mM0.1990mL0.9950mL1.9901mL請根據產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，避免反復凍融造成的產品失效。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?內使?，-20°C儲存時，請在1個?內使?。體內實驗請根據您的實驗動物和給藥?式選擇適當的溶解?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：(為保證實驗結果的可靠性，澄的儲備液可以根據儲存條件，適當保存；體內實驗的?作液，建議您現?現配，當天使?；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沉淀、析出現象，可以通過加熱和/或超聲的?式助溶)1.請依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥2.5mg/mL(4.98mM);Clearsolution1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE2.請依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.5mg/mL(4.98mM);Clearsolution3.請依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(4.98mM);Clearsolution4.請依序添加每種溶劑：5%DMSO>>40%PEG300>>5%Tween-80>>50%salineSolubility:2.5mg/mL(4.98mM);Suspendedsolution;NeedultrasonicBIOLOGICALACTIVITY?物活性LXH254?種有效的、具有?服活性的II型BRAF和CRAF抑制劑，對CRAF和BRAF的IC50值分別為0.072和0.21nM[2]。IC50&TargetCRAFBrafARAFp38α0.072nM(IC50)0.21nM(IC50)6.4nM(IC50)2.1μM(IC50)Abl14.9μM(IC50)體外研究LXH254(CompoundA)isanadenosinetriphosphate(ATP)-competitiveinhibitorofBRAF(alsoreferredtohereinasb-RAForb-Raf)andCRAF(alsoreferredtohereinasc-RAForc-Raf)proteinkinases.Throughoutthepresentdisclosure,LXH254isalsoreferredtoasac-RAF(orCRAF)inhibitororaC-RAF/c-Rafkinaseinhibitor.Incell-basedassays,LXH254hasdemonstratedanti-proliferativeactivityincelllinesthatcontainavarietyofmutationsthatactivateMAPKsignaling.Moreover,LXH254isaType2ATP-competitiveinhibitorofbothB-RafandC-Rafthatkeepsthekinasepocketinaninactiveconformation,therebyreducingtheparadoxicalactivationseenwithmanyB-Rafinhibitors,andblockingmutantRAS-drivensignalingandcellproliferation[1].LXH254(0-10μM,1h)inhibitsbothmonomericanddimericRAFandpromotesRAFdimerformation[2].LXH254hasreducedabilitytosuppressMAPKsignalingdrivenbyARAFandfurtherthatthecontributionofARAFtoMAPKsignalingincreasesintheabsenceofCRAFexpression[2].LXH254showsmoresensitivitywhencellslackARAF[2].WesternBlotAnalysis[2]CellLine:HCT116,MEL-JUSO,MiaPaCa-2,A375(BRAFV600E),andHCT116(KRASG13D)Concentration:0-10μMIncubationTime:1hResult:PromotedB/CRAFheterodimerformation.DisplayedsimilarinhibitionofmonomericBRAFV600andwild-typedimericRAF(IC50forp-ERKlevelsof59and78nmol/LinA-375andHCT116cells,respectively).CellProliferationAssay[2]2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemECellLine:TwoNRAS-mutantmelanomacelllines(MEL-JUSOandSK-MEL-30),threeKRAS-mutantcelllines(COR-L23,MIAPaCa-2,andHCT116),andderivedvariantslackingexpressionofeitherARAF,BRAF,orCRAF.Concentration:0-10μMIncubationTime:24hResult:ThesensitivitywasincreasedrelativetoparentalcelllinesinallmodelstestedbylossofARAFexpression.體內研究TreatmentwithLXH254(CompoundA)generatestumorregressioninseveralKRAS-mutantmodelsincludingtheNSCLC-derivedCalu-6(KRASQ61K)andNCI-H358(KRASG12C).LXH254exhibitsefficacyinnumerousMAPK-drivenhumancancercelllinesandinxenografttumorsrepresentingmodeltumorsharboringhumanlesionsinKRAS,NRASandBRAFoncogenes[1].LXH254showssignificantantitumoractivityinmodelsharboringBRAFmutationseitheraloneorcoincidentwitheitheractivatedNRASorKRAS,andRASmutantslackingARAFaremoresensitivetoLXH254[2].AnimalModel:Outbredathymic(nu/nu)femalemiceandSCIDBeigemice;BRAF-,NRAS-,andKRAS-mutantxenograftmodels,aswellasaRAS/RAFwild-typemodel[2]Dosage:100mg/kgAdministration:Orally,dailyResult:SignificantlydecreasedtumorvolumeinmodelsharboringBRAFmutationseitheraloneorcoincidentwitheitheractivatedNRASorKRAS,slightlydecreasedtumorvolumeinKRASmodel.戶使?本產品發(fā)表的科研?獻?BiomedChromatogr.2021Feb;35(2):e4968.?ResearchSquarePrint.October27th,2022.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].CAPONIGRO,Giordano,etal.THERAPEUTICCOMBINATIONSCOMPRISINGARAFINHIBITORANDAERKINHIBITOR.WO2018051306A120180322[2].Kelli-AnnMonaco,etal.LXH254,aPotentandSelectiveARAF-SparingInhibitorofBRAFandCRAFfortheTreatmentofMAPK-DrivenTumors.ClinCancerRes.2021Apr1;27(7):2061-2073.McePdfHeight3/3Maste