Lorlatinib-PF-06463922-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemELorlatinibCat.No.:HY-12215CASNo.:1454846-35-5Synonyms:PF-06463922分⼦式:C₂₁H₁₉FN₆O₂分⼦量:406.41作⽤靶点:Anaplasticlymphomakinase(ALK);ROSKinase;Apoptosis作⽤通路:ProteinTyrosineKinase/RTK;Apoptosis储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:≥28mg/mL(68.90mM)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制备储备液1mM2.4606mL12.3028mL24.6057mL5mM0.4921mL2.4606mL4.9211mL10mM0.2461mL1.2303mL2.4606mL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)1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemE1.请依序添加每种溶剂：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥2.5mg/mL(6.15mM);Clearsolution2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:2.5mg/mL(6.15mM);Suspendedsolution;Needultrasonic3.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(6.15mM);Clearsolution4.请依序添加每种溶剂：5%DMSO>>40%PEG300>>5%Tween-80>>50%salineSolubility:≥2.5mg/mL(6.15mM);ClearsolutionBIOLOGICALACTIVITY⽣物活性Lorlatinib(PF-06463922)⼀种具有⼝服活性，选择性，脑渗透性和ATP竞争性的ROS1/ALK抑制剂。Lorlatinib对于ROS1，野⽣型ALK和ALKL1196M的Ki分别为<0.025nM，<0.07nM和0.7nM。Lorlatinib具有抗癌活性。IC50&TargetKi:<0.02nM(ROS1),<0.07nM(ALKWT),0.7nM(ALKL1196M)体外研究Lorlatinib(PF-06463922)demonstratessignificantcellactivityagainstALKandalargesetofALKclinicalmutationswithIC50rangingfrom0.2nM-77nM[1].LorlatinibsignificantlyinhibitscellproliferationandinducescellapoptosisintheHCC78humanNSCLCcellsharboringSLC34A2-ROS1fusionsandtheBaF3-CD74-ROS1cellsexpressinghumanCD74-ROS1.LorlatinibalsoshowspotentgrowthinhibitoryactivityandinducesapoptosisintheNSCLCcellsharboringeithernon-mutantALKormutantALKfusions[2].体内研究Inrats,Lorlatinib(PF-06463922)displayslowplasmaclearance,amoderatevolumeofdistribution,areasonablehalf-life,lowpropensityforp-glycoprotein1-mediatedeffluxandabioavailabilityof100%[1].Invivo,LorlatinibshowscytoreductiveantitumorefficacyintheNIH3T3xenograftmodelsexpressinghumanCD74-ROS1andFig-ROS1viainhibitioninROS1phosphorylationandthedownstreamsignalingmolecules,aswellasinhibitionofthecellcycleproteinCyclinD1intumors.LorlatinibalsodemonstratesmarkedantitumoractivityinmicebearingtumorxenograftsexpressingEML4-ALK,EML4-ALK-L1196M,EML4-ALK-G1269A,EML4-ALK-G1202RorNPM-ALK[2].PROTOCOLCellAssay[2]Cellsareseededin96-wellplatesingrowthmediumcontaining10%FBSandareculturedovernightat37°C.Thefollowingday,serialdilutionsofLorlatiniborappropriatecontrolsareaddedtothedesignatedwells,andcellsareincubatedat37°Cfor72h.ACellTiter-Gloassayisperformedtodeterminetherelativecellnumbers.IC50valuesarecalculatedbyconcentration-responsecurvefittingusingafour-parameteranalyticalmethod.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalDenovoGBMtumorigenesisisinitiatedinLSL-FIG-ROS1;Cdkn2a−/−;LSL-LucmicethroughintracranialAdministration[2]stereotacticinjectionsofAdeno-Creasdescribedpreviously.TumordevelopmentismonitoredusingBLIas2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEdescribedbelow.Oncetumorsreachagivensize(107p-1·s-1·cm-2·sr-1),animalsarerandomLyenrolledintovehiclecontrolor3-,7-,or14-dtreatmentwiththeindicateddosesofLorlatinib.Drugisadministeredthroughs.c.implantedAlzetosmoticpumps.Aftertreatment,micearekilled,GBMtumorsaremicrodissected,andtissuesareflash-frozeninliquidN2.Theremainingbrainsareprocessedforhistology.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.户使⽤本产品发表的科研⽂献•NatCancer.2022Oct;3(10):1211-1227.•NatCommun.2017Oct30;8(1):1197.•EMBOMolMed.2020Jul7;12(7):e11099.•Oncogene.2022Sep5.•Oncogene.2022May;41(20):2789-2797.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].JohnsonTW,etal.Discoveryof(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile(PF-06463922),amacrocyclicinhibitorofanaplasticlymphomakinas[2].ZouHY,etal.PF-06463922isapotentandselectivenext-generationROS1/ALKinhibitorcapableofblockingPF-02341066-resistantROS1mutations.ProcNatlAcadSc