Lorlatinib-PF-06463922-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemELorlatinibCat.No.:HY-12215CASNo.:1454846-35-5Synonyms:PF-06463922分?式:C??H??FN?O?分?量:406.41作?靶點(diǎn):Anaplasticlymphomakinase(ALK);ROSKinase;Apoptosis作?通路:ProteinTyrosineKinase/RTK;Apoptosis儲(chǔ)存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數(shù)據(jù)體外實(shí)驗(yàn)DMSO:≥28mg/mL(68.90mM)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM2.4606mL12.3028mL24.6057mL5mM0.4921mL2.4606mL4.9211mL10mM0.2461mL1.2303mL2.4606mL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(chǔ)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(chǔ)備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲(chǔ)存時(shí)，請?jiān)?個(gè)?內(nèi)使?，-20°C儲(chǔ)存時(shí)，請?jiān)?個(gè)?內(nèi)使?。體內(nèi)實(shí)驗(yàn)請根據(jù)您的實(shí)驗(yàn)動(dòng)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(chǔ)備液，再依次添加助溶劑：(為保證實(shí)驗(yàn)結(jié)果的可靠性，澄的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)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:≥2.5mg/mL(6.15mM);Clearsolution2.請依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:2.5mg/mL(6.15mM);Suspendedsolution;Needultrasonic3.請依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(6.15mM);Clearsolution4.請依序添加每種溶劑：5%DMSO>>40%PEG300>>5%Tween-80>>50%salineSolubility:≥2.5mg/mL(6.15mM);ClearsolutionBIOLOGICALACTIVITY?物活性Lorlatinib(PF-06463922)?種具有?服活性，選擇性，腦滲透性和ATP競爭性的ROS1/ALK抑制劑。Lorlatinib對于ROS1，野?型ALK和ALKL1196M的Ki分別為<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)體外研究Lorlatinib(PF-06463922)demonstratessignificantcellactivityagainstALKandalargesetofALKclinicalmutationswithIC50rangingfrom0.2nM-77nM[1].LorlatinibsignificantlyinhibitscellproliferationandinducescellapoptosisintheHCC78humanNSCLCcellsharboringSLC34A2-ROS1fusionsandtheBaF3-CD74-ROS1cellsexpressinghumanCD74-ROS1.LorlatinibalsoshowspotentgrowthinhibitoryactivityandinducesapoptosisintheNSCLCcellsharboringeithernon-mutantALKormutantALKfusions[2].體內(nèi)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?邊的抑制劑?師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.戶使?本產(chǎn)品發(fā)表的科研?獻(xiàn)?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