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MedKoo Biosciences/PX-478 HCl/202350/1g

PX-478isHIF-1alphainhibitor,isalsoanorallyactivesmallmoleculewithpotentialantineoplasticactivity.Althoughitsmechanismofactionhasyettobefullyelucidated,HIF1-alphainhibitorPX-478appearstoinhibithypoxia-inducIBLefactor1-alpha(HIF1A)expression,whichmayresultindecreasedexpressionofHIF1Adownstreamtargetgenesimportanttotumorgrowthandsurvival,areductionintumorcellproliferation,andtheinductionoftumorcellapoptosis.TheinhibitoryeffectofthisagentisindependentofthetumorsuppressorgenesVHLandp53andmayberelatedtoderangementsinglucoseuptakeandmetabolismduetoinhibitionofglucosetransporter-1(Glut-1).PX-478hasexcellentactivityagainstestablishedhumantumorxenografts,providingtumorregressionswithprolongedgrowthdelayswhichcorrelatepositivelywithHIF-1levels.PX-478isahighlywatersolublemolecule,withgoodi.v.,i.p.andp.o.antitumoractivity.Itisrapidlyabsorbedfollowingoralandi.p.admiNISTrationandgivesexcellentCmaxandAUCviatheseroutes.

MedKooCat#:202350
Name:PX-478HCl
CAS#:685898-44-6(HClsalt);685847-78-3(freebase)
ChemicalFormula:C13H20Cl4N2O3
ExactMass:
MolecularWeight:394.11
ElementalAnalysis:C,39.62;H,5.12;Cl,35.98;N,7.11;O,12.18


Synonym:PX478;PX-478;PX478;PX478HCl.

IUPAC/ChemicalName:(S)-4-(2-amino-2-carboxyethyl)-N,N-bis(2-chloroethyl)anilineoxidedihydrochloride

InChiKey:GIGCDIVNDFQKRA-LTCKWSDVSA-N

InChiCode:InChI=1S/C13H18Cl2N2O3.2ClH/c14-5-7-17(20,8-6-15)11-3-1-10(2-4-11)9-12(16)13(18)19;;/h1-4,12H,5-9,16H2,(H,18,19);2*1H/t12-;;/m0../s1

SMILESCode:ClCC[N+](CCCl)([O-])C1=CC=C(C[C@H](N)C(O)=O)C=C1.[H]Cl.[H]Cl


TechnicalData

Appearance:
Brownsolidpowder(wax-likesolidorsemi-solidafterabsorbmoisturefromair).PX478HClishighlyhygroscopic,andmaybecomewax-likematerialafterexposinginair,whichwillnotimpactthestABIlity.

Purity:
>95%(orrefertotheCertificateofAnalysis)

CertificateofAnalysis:
ViewCoA:previousbatch,Lot#:KBB20130809
ViewCoA:currentbatch,Lot#SSC50911

QCData:
ViewQCdata:previousbatch,Lot#:KBB20130809
ViewQCdata:currentbatch,Lot#SSC50911

SafetyDataSheet(MSDS):
ViewMaterialSafetyDataSheet(MSDS)

ShippingCondition:
Shippedunderambienttemperatureasnon-hazardouschemical.ThisproductisstableenoughforafewweeksduringordinaryshippingandtimespentinCustoms.

StorageCondition:
Dry,darkandat0-4Cforshortterm(daystoweeks)or-20Cforlongterm(monthstoyears).

Solubility:
Solubleinwater.PX-478wasfoundtobenotstableatbasicbuffer,andstableinacidicbuffer.

ShelfLife:
>5yearsifstoredproperly

DrugFormulation:
ThisdrugmaybeformulatedinPBSbuffer.Forlongtermstabilityconsideration,werecommendtopreparePX478stocksolutioninpH4.0buffer.ThestocksolutionmaybedilutedbyPBSbeforeusing.

StockSolutionStorage:
0-4Cforshortterm(daystoweeks),or-20Cforlongterm(months).

HarmonizedSystemCode:
293490


AdditionalInformation

 
StabilityofPX-478: AccordingtoresearchersfromProlXPharmaceuticals,chemicalstabilityofPX-478undervariabletemperatureandlightconditionsshowed100%recoveryforgreaterthan6months.PX-478,aseitheranamorphousorcrystallinehydrochloridesaltishighlywatersoluble.ExaminationofpHstabilityprovidedevidenceofbaselability,howeverexcellentstabilityinsolutionsofpH<3witht1/2of26to2643daysat4°C.Neutral,isotonicbuffereddosingsolutionhadsufficientstabilitytoallowi.v.administrationforthetoxicologyandkineticsstudiesinmice,rats,anddogswherethemaximumtolerabledoseforfivedayi.v.treatmentwasfoundtobe100,35and20mg/kg,respectively. (source:http://aacrmeetingabstracts.org/cgi/content/abstract/2004/1/486-b).
 
Activityobservedinanimalmodelstudy:PX-478hasbeenshowntohaveefficacyagainstanumberofhumancancerxenograftmodels,withsignificantregressionsandgrowthdelaysinOvCar-3(ovarian),SHP-77(smallcelllung),PC-3(prostate),DU-145(prostate),MCF-7(breast),andCaki-1(renal).PX-478suppressesconstitutiveandhypoxiainducedlevelsofHIF-1aincancercells,whileleavingotherubiquitinregulatedproteinsunaffected.ThroughHIF-1ainhibition,PX-478inhibitstheexpressionofVEGFandtheglucosetransporterGlut-1,resultinginmassivetumourapoptosisWhentumours(xenograftmodelsinmice)arebeingtreatedwithPX-478,theefficiencyoftumourkillingcorrelateswithinherenttumourHIF-1aexpression.(source:http://pharmalicensing.com).
 
ToxicityofPX-478:Theprimarytoxicologicalindicatorsweremyelosuppressionandrapidlyreversibleweightlossthatcorrelatedwithfoodintake.ThebioanalyticprotocolandassaydevelopedforidentificationofPX-478andmetabolitesinBIOLOGicalsamplesdemonstratedexcellentfrozenandrefrigeratedstabilityofPX-478onceisolated. Oralandi.p.administrationofPX-478tomiceshowexcellentbioavailabilityof86%and91%,respectively.Theterminalhalflifevaluesforparentdrugweredeterminedinmiceanddogstobe60minutesand8minutes,respectively.Clearanceandvolumeofdistributioninmiceanddogswerefoundtobe4.7and15.6ml/min/kgand380and184ml/kg,respectively.ProteinbindingstudiesofPX-478inmiceshowednomeasurablebinding. (source:http://aacrmeetingabstracts.org/cgi/content/abstract/2004/1/486-b).
 
MechanismofP-478:PX-478istheN-oxideformoftheapprovedanticancerdrug melphalan,  PX-478wasreportedtosuppressHIF-1αlevelsinhumantumorxenograftsandinhibittheexpressionofHIF-1targetgenesincludingvascularendothelialgrowthfactor(VEGF)andtheglucosetransporter-1.PX-478hadmarkedantitumoractivityagainstevenlargetumorxenografts,whichcorrelatedpositivelywithHIF-1αlevels.Eventhoughtheupstreamtargetshavenotbeenfullyelucidated,PX-478inhibitedHIF-1αatmultiplelevelsthattogetherorindividuallymightcontributetoitsantitumoractivityagainstHIF-1α-expressingtumors.ItwasreportedthatPX-478inhibitedHIF-1αproteinlevelsandHIF-1transactivatingactivityinavarietyofcancercelllines.TheinhibitionoccurredinbothnormoxicandhypoxicconditionsanddidnotrequirepVHLorp53. 
 
ThreemechanismswereidentifiedascontributingtothedecreaseinHIF-1αlevelsbyPX-478:reductioninHIF-1αmRNAlevels,andinhibitionofHIF-1αtranslationplaymajorroles;inhibitionofHIF-1αdeubiquitination,appearstoplayaminorrole.HIF-1αwasup-regulatedinirrADIatedtumorsandthusmightserveasapromisingtargetforradiosensitization.PX-478reducedHIF-1αproteinlevelsandsignalinginvitroinadose-dependentmannerandprovideddirectradiosensitizationofhypoxiccancercellsinclonogenicsurvivalassaysusingC6glioma,HN5andUMSCCa10squamouscells,andPanc-1pancreaticadenocarcinomacelllines.  Ofnote,PX-478yieldedstrikinginvivotumorsensitizationtoasingle-doseirradiation,preventedpostradiationHIF-1signaling,andabrogateddownstreamstromaladaptationinC6andHN5reporterxenografts.(source:LeeK,KimHM.AnovelapproachtocancertherapyusingPX-478asaHIF-1αinhibitor.ArchPharmRes.2011Oct;34(10):1583-5.)
 
PhaseItrialsofP-478: APhaseItrialwasdoneattwositesintheUSandtheresultwasreportedatthe2010ASCOAnnualMeeting.ThePhaseItrialofPX-478wasanopen-label,doseescalationtrialin41patientswithadvancedcancerthatwasdesignedtoexaminesafety,tolerability,pharmacokinetics,pharmacodynamicsandantitumoractivity.PX-478wasadministeredorallyondays1-5ofa21daycycleatdosesrangingfrom1mg/m2to88.2mg/m2.Adverseeventsoccurringinmorethan10percentofpatientswerenausea,fatigue,diarrheaandvomiting.OnepatientexperiencedprolongedGrade3thrombocytopeniaatthehighestdoselevel.Thirteenof37evaluablepatients(35%)hadstabledisease.Pharmacodynamicstudiesrevealeddose-proportionalinhibitionofHIF-1αlevels.PharmacokineticstudiesdemonstratedlowlevelsofPX-478withevidenceforconversiontomelphalanandothermetabolites.TheresultwaspromisinginthatclinicaltreatmentwithPX-478wasassociatedwitharelativelyhighproportionofpatientsachievingstablediseaseandadose-dependentinhibitionofHIF-1α.MetaboliteidentificationandrelatedmetabolismstudiesmightbedonetoidentifymetabolicpathwaysandactiveentitiesfromPX-478besidesinactivemelphalan. Conclusively,HIF-1αwasproventobeavalidtargetofcancertherapyandmodulatesmultipletumOrigenicprocesses.TheinformationfrompreclinicalandclinicaltrialsofPX-478willbeusefulfordevelopinganovelapproachtocancertherapywithHIF-1αinhibitorsandgivepositiveimpactstofollowingdevelopmentsandappilicationsofHIFinhibitors. (source:LeeK,KimHM.AnovelapproachtocancertherapyusingPX-478asaHIF-1αinhibitor.ArchPharmRes.2011Oct;34(10):1583-5.)
 
 
 


References

1:LeeK,KimHM.AnovelapproachtocancertherapyusingPX-478asaHIF-1αinhibitor.ArchPharmRes.2011Oct;34(10):1583-5.doi:10.1007/s12272-011-1021-3.Review.PubMedPMID:22076756.

2:SchwartzDL,BanksonJA,LemosRJr,LaiSY,ThittaiAK,HeY,HostetterG,DemeureMJ,VonHoffDD,PowisG.RadiosensitizationandstromalimagingresponsecorrelatesfortheHIF-1inhibitorPX-478givenwithorwithoutchemotherapyinpancreaticcancer.MolCancerTher.2010Jul;9(7):2057-67.doi:10.1158/1535-7163.MCT-09-0768.Epub2010Jun29.PubMedPMID:20587661;PubMedCentralPMCID:PMC2935253.

3:JacobyJJ,ErezB,KorshunovaMV,WilliamsRR,FurutaniK,TakahashiO,KirkpatrickL,LippmanSM,PowisG,O'ReillyMS,HerbstRS.TreatmentwithHIF-1alphaantagonistPX-478inhibitsprogressionandspreadoforthotopichumansmallcelllungcancerandlungadenocarcinomainmice.JThoracOncol.2010Jul;5(7):940-9.doi:10.1097/JTO.0b013e3181dc211f.PubMedPMID:20512076;PubMedCentralPMCID:PMC3782111.

4:SchwartzDL,PowisG,Thitai-KumarA,HeY,BanksonJ,WilliamsR,LemosR,OhJ,VolginA,SoghomonyanS,NishiiR,AlauddinM,MukhopadhayU,PengZ,BornmannW,GelovaniJ.Theselectivehypoxiainduciblefactor-1inhibitorPX-478providesinvivoradiosensitizationthroughtumorstromaleffects.MolCancerTher.2009Apr;8(4):947-58.doi:10.1158/1535-7163.MCT-08-0981.PubMedPMID:19372568;PubMedCentralPMCID:PMC2908257.

5:PalayoorST,MitchellJB,CernaD,DegraffW,John-AryankalayilM,ColemanCN.PX-478,aninhibitorofhypoxia-induciblefactor-1alpha,enhancesradiosensitivityofprostatecarcinomacells.IntJCancer.2008Nov15;123(10):2430-7.doi:10.1002/ijc.23807.PubMedPMID:18729192.

6:KohMY,Spivak-KroizmanT,VenturiniS,WelshS,WilliamsRR,KirkpatrickDL,PowisG.MolecularmechanismsfortheactivityofPX-478,anantitumorinhibitorofthehypoxia-induciblefactor-1alpha.MolCancerTher.2008Jan;7(1):90-100.doi:10.1158/1535-7163.MCT-07-0463.PubMedPMID:18202012.

7:JordanBF,BlackK,RobeyIF,RunquistM,PowisG,GilliesRJ.MetabolitechangesinHT-29xenografttumorsfollowingHIF-1alphainhibitionwithPX-478asstudiedbyMRspectroscopyinvivoandexvivo.NMRBiomed.2005Nov;18(7):430-9.PubMedPMID:16206237.

8:JordanBF,RunquistM,RaghunandN,BakerA,WilliamsR,KirkpatrickL,PowisG,GilliesRJ.Dynamiccontrast-enhancedanddiffusionMRIshowrapidanddramaticchangesintumormicroenvironmentinresponsetoinhibitionofHIF-1alphausingPX-478.Neoplasia.2005May;7(5):475-85.PubMedPMID:15967100;PubMedCentralPMCID:PMC1501160.

9:WelshS,WilliamsR,KirkpatrickL,Paine-MurrietaG,PowisG.AntitumoractivityandpharmacodynamicpropertiesofPX-478,aninhibitorofhypoxia-induciblefactor-1alpha.MolCancerTher.2004Mar;3(3):233-44.PubMedPMID:15026543. 

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