Larotrectinib-sulfate-LOXO-101-sulfate-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemELarotrectinibsulfateCat.No.:HY-12866ACASNo.:1223405-08-0Synonyms:LOXO-101sulfate;ARRY-470sulfate分⼦式:C₂₁H₂₄F₂N₆O₆S分⼦量:526.51作⽤靶点:TrkReceptor;Apoptosis作⽤通路:NeuronalSignaling;ProteinTyrosineKinase/RTK;Apoptosis储存⽅式:4°C,sealedstorage,awayfrommoisture*Insolvent:-80°C,6months;-20°C,1month(sealed

storage,awayfrommoisture)溶解性数据体外实验DMSO:50mg/mL(94.96mM;Needultrasonic)H2O:2mg/mL(3.80mM;ultrasonicandadjustpHto2with1MHCl)MassSolvent1mg5mg10mgConcentration制备储备液1mM1.8993mL9.4965mL18.9930mL5mM0.3799mL1.8993mL3.7986mL10mM0.1899mL0.9496mL1.8993mL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(sealedstorage,awayfrommoisture)。-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%saline1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemESolubility:≥3.25mg/mL(6.17mM);Clearsolution2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥3.25mg/mL(6.17mM);Clearsolution3.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥3.25mg/mL(6.17mM);Clearsolution4.请依序添加每种溶剂：5%DMSO>>40%PEG300>>5%Tween-80>>50%salineSolubility:≥2.5mg/mL(4.75mM);Clearsolution5.请依序添加每种溶剂：5%DMSO>>95%(20%SBE-β-CDinsaline)Solubility:≥2.5mg/mL(4.75mM);ClearsolutionBIOLOGICALACTIVITY⽣物活性Larotrectinibsulfate(LOXO-101sulfate;ARRY-470sulfate)⼀种ATP竞争性的、⼝服选择性抑制剂，对原肌凝蛋⽩相关激酶(TRK)家族受体的三个亚型(TRKA，B和C)具有纳尔级别的50%抑制浓度。IC50&TargetTrkATrkBTrkC体外研究Larotrectinib(LOXO-101)isanATP-competitiveoralinhibitorofthetropomyosin-relatedkinase(TRK)familyofreceptorkinases(TRKA,B,andC),withlownanomolar50%inhibitoryconcentrationsagainstallthreeisoforms,and1,000-foldorgreaterselectivityrelativetootherkinases[1][2].MeasurementofproliferationfollowingtreatmentwithLarotrectinib(LOXO-101)demonstratesadose-dependentinhibitionofcellproliferationinallthreecelllines.TheIC50islessthan100nMforCUTO-3.29andlessthan10nMforKM12andMO-91consistentwiththeknownpotencyofthisdrugfortheTRKkinasefamily[3].体内研究Inratandmonkeystudies,Larotrectinib(LOXO-101)demonstrates33-100%oralbioavailabilityand60-65%plasmaproteinbinding.Ithaslowbrainpenetration,andiswelltoleratedin28day(d)GLPtoxicologystudies.Asingledose(30mg/kg)ofLarotrectinib(LOXO-101)reducestyrosinephosphorylationofTRKAanddownstreamsignaltransduction(pERK)inthetumor>80%[1].AthymicnudemiceinjectedwithKM12cellsaretreatedwithLarotrectinibsulfateorallydailyfor2weeks.Dose-dependenttumorinhibitionisobserveddemonstratingtheabilityofthisselectivecompoundtoinhibittumorgrowthinvivo[4].Larotrectinib(LOXO-101)(200mg/kg/dayp.oforsixweeks)reducesleukemicinfiltrationtoundetectablelevelsinthebonemarrowandspleencomparedtovehicle-treatedmice.MicetreatedwithLarotrectinibsulfatearestillaliveandleukemia-freefourweeksafterthecessationoftreatment,asdeterminedbyXenogenimaging[5].PROTOCOLAnimalMice[4]Administration[4]Athymicnudemiceareusedthroughoutthestudy.5×105KM12cellsareinjectedsubcutaneouslyintothedorsalflankareaofthemice.Tumorvolumeismonitoredbydirectmeasurementwithcalipersandcalculatedbytheformula:length×(width2)/2.Followingtheestablishmentoftumorandwhenthetumorsizeisbetween150-200mm2,micearerandomlyselectedtoreceivediluent,60mg/kg/doseor200mg/kg/doseofLarotrectinib(LOXO-101).Larotrectinib(LOXO-101)isadministeredbyoralgavageoncedailyfor14days.2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEAfterthelastdose,tissueandbloodarecollectedat3,6and24hourspost-treatment[4].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.户使⽤本产品发表的科研⽂献•MolOncol.2022Oct1.•EurJMedChem.2020Aug30;207:112744.•MolCancerTher.2021Oct8;molcanther.MCT-21-0632-A.2021.•JAnalSciTechnol.2020Jun.•bioRxiv.04Nov2021.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].DoebeleRC,etal.AnOncogenicNTRKFusioninaPatientwithSoft-TissueSarcomawithResponsetotheTropomyosin-RelatedKinaseInhibitorLOXO-101.CancerDiscov.2015Oct;5(10):1049-57.[2].KarynBouhana,etal.LOXO-101,apanTRKinhibitor,ForTheTreatmentOfTRK-drivenCancers.[3].NagasubramanianR,etal.InfantileFibrosarcomaWithNTRK3-ETV6FusionSuccessfullyTreatedWiththeTropomyosin-RelatedKinaseInhibitorLOXO-101.PediatrBloodCancer.2016Aug;63(8):1468-70.[4].KathrynG,etal.GeneticModelingandTherapeuticTargetingofETV6-NTRK3withLoxo-101inAcut