LXH254-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemELXH254Cat.No.:HY-112089CASNo.:1800398-38-2分⼦式:C₂₅H₂₅F₃N₄O₄分⼦量:502.49作⽤靶点:Raf;p38MAPK;Bcr-Abl作⽤通路:MAPK/ERKPathway;ProteinTyrosineKinase/RTK储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:100mg/mL(199.01mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制备储备液1mM1.9901mL9.9504mL19.9009mL5mM0.3980mL1.9901mL3.9802mL10mM0.1990mL0.9950mL1.9901mL请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；⼀旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存⽅式和期限：-80°C,6months;-20°C,1month。-80°C储存时，请在6个⽉内使⽤，-20°C储存时，请在1个⽉内使⽤。体内实验请根据您的实验动物和给药⽅式选择适当的溶解⽅案。以下溶解⽅案都请先按照InVitro⽅式配制澄的储备液，再依次添加助溶剂：(为保证实验结果的可靠性，澄的储备液可以根据储存条件，适当保存；体内实验的⼯作液，建议您现⽤现配，当天使⽤；以下溶剂前显⽰的百分⽐指该溶剂在您配制终溶液中的体积占⽐；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的⽅式助溶)1.请依序添加每种溶剂：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥2.5mg/mL(4.98mM);Clearsolution1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemE2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.5mg/mL(4.98mM);Clearsolution3.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(4.98mM);Clearsolution4.请依序添加每种溶剂：5%DMSO>>40%PEG300>>5%Tween-80>>50%salineSolubility:2.5mg/mL(4.98mM);Suspendedsolution;NeedultrasonicBIOLOGICALACTIVITY⽣物活性LXH254⼀种有效的、具有⼝服活性的II型BRAF和CRAF抑制剂，对CRAF和BRAF的IC50值分别为0.072和0.21nM[2]。IC50&TargetCRAFBrafARAFp38α0.072nM(IC50)0.21nM(IC50)6.4nM(IC50)2.1μM(IC50)Abl14.9μM(IC50)体外研究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—您⾝边的抑制剂⼤师www.MedChemECellLine:TwoNRAS-mutantmelanomacelllines(MEL-JUSOandSK-MEL-30),threeKRAS-mutantcelllines(COR-L23,MIAPaCa-2,andHCT116),andderivedvariantslackingexpressionofeitherARAF,BRAF,orCRAF.Concentration:0-10µMIncubationTime:24hResult:ThesensitivitywasincreasedrelativetoparentalcelllinesinallmodelstestedbylossofARAFexpression.体内研究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.户使⽤本产品发表的科研⽂献•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