Cobimetinib,alsoknownasGDC-0973andXL-518,isanorallybioavailablesmall-moleculeinhibitorofmitogen-activatedproteinkinasekinase1(MAP2K1orMEK1),withpotentialantineoplasticactivity.MEKinhibitorGDC-0973specificallybindstoandinhibitsthecatalyticactivityofMEK1,resultingininhibitionofextracellularsignal-relatedkinase2(ERK2)phosphorylationandactivationanddecreasedtumorcellproliferation.PreclinicalstudieshavedemonstratedthatthisagentiseffectiveininhibitingthegrowthoftumorcellsbearingaB-RAFmutation,whichhasbeenfoundtobeassociatedwithmanytumortypes.

MedKooCat#:203185
Name:Cobimetinib
CAS#:934660-93-2(freebase)
ChemicalFormula:C22H22F3IN2O2
ExactMass:530.06781
MolecularWeight:530.32196
ElementalAnalysis:C,49.83;H,4.18;F,10.75;I,23.93;N,5.28;O,6.03


RelatedCAS#:1369665-02-0(fumarate) 934660-93-2(freebase)  

Synonym:XL518;XL518;XL-518;GDC0973;GDC0973;GDC-0973;cobimetinib.

IUPAC/ChemicalName:(S)-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)phenyl)(3-hydroxy-3-(piperidin-2-yl)cyclobutyl)methanone.

InChiKey:FIAWSLMDMMCNMU-HHCSFTFJSA-N

InChiCode:InChI=1S/C22H22F3IN2O2/c23-15-6-5-14(20(19(15)25)28-17-7-4-13(26)9-16(17)24)21(29)12-10-22(30,11-12)18-3-1-2-8-27-18/h4-7,9,12,18,27-28,30H,1-3,8,10-11H2/t12?,18-,22?/m0/s1

SMILESCode:O=C(C1=CC=C(F)C(F)=C1NC2=CC=C(I)C=C2F)C3CC([C@H]4NCCCC4)(O)C3


TechnicalData

Appearance:
whitesolidpowder

Purity:
>98%(orrefertotheCertificateofAnalysis)

ShippingCondition:
Shippedunderambienttemperatureasnon-hazardouschemical.ThisproductisstableenoughforafewweeksduringordinaryshippingandtimespentinCustoms.

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

Solubility:
SolubleinDMSO,notinwater

ShelfLife:
>2yearsifstoredproperly

DrugFormulation:
ThisdrugmaybeformulatedinDMSO

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

HarmonizedSystemCode:
293490


AdditionalInformation

GDC-0973isapotentandhighlyselectiveinhibitorofMEK(Figure1A),withabiochemicalIC50of4.2nMagainstMEK1.Inbiochemicalassays,GDC-0973demonstrated>100-foldselectivityforMEKwhentestedagainstapanelof>100serine-threonineandtyrosinekinases.GDC-0973showsstrongcellularpotencyinabroadpaneloftumortypes,particularlyinBRAForKRASmutantcancercelllines
 
Currentdeveloper:  Genentech
 
 


References

1:ChooEF,NgCM,BerryL,BelvinM,Lewin-KohN,MerchantM,SalphatiL.PK-PDmodelingofcombinationefficacyeffectfromadministrationoftheMEKinhibitorGDC-0973andPI3KinhibitorGDC-0941inA2058xenografts.CancerChemotherPharmacol.2013Jan;71(1):133-43.doi:10.1007/s00280-012-1988-6.Epub2012Oct7.PubMedPMID:23053270.

2:BaudyAR,DoganT,Flores-MercadoJE,HoeflichKP,SuF,vanBruggenN,WilliamsSP.FDG-PETisagoodbiomarkerofbothearlyresponseandacquiredresistanceinBRAFV600mutantmelanomastreatedwithvemurafenibandtheMEKinhibitorGDC-0973.EJNMMIRes.2012May31;2(1):22.doi:10.1186/2191-219X-2-22.PubMedPMID:22651703;PubMedCentralPMCID:PMC3405466.

3:RiceKD,AayN,AnandNK,BlazeyCM,BowlesOJ,BusseniusJ,CostanzoS,CurtisJK,DefinaSC,DubenkoL,EngstS,JoshiAA,KennedyAR,KimAI,KoltunES,LougheedJC,ManaloJC,MartiniJF,NussJM,PetoCJ,TsangTH,YuP,JohnstonS.NovelCarboxamide-BasedAllostericMEKInhibitors:DiscoveryandOptimizationEffortstowardXL518(GDC-0973).ACSMedChemLett.2012Apr9;3(5):416-21.doi:10.1021/ml300049d.eCollection2012May10.PubMedPMID:24900486;PubMedCentralPMCID:PMC4025802.

4:WongH,VernilletL,PetersonA,WareJA,LeeL,MartiniJF,YuP,LiC,DelRosarioG,ChooEF,HoeflichKP,ShiY,AftabBT,AoyamaR,LamST,BelvinM,PrescottJ.Bridgingthegapbetweenpreclinicalandclinicalstudiesusingpharmacokinetic-pharmacodynamicmodeling:ananalysisofGDC-0973,aMEKinhibitor.ClinCancerRes.2012Jun1;18(11):3090-9.doi:10.1158/1078-0432.CCR-12-0445.Epub2012Apr10.PubMedPMID:22496205.

5:ChooEF,BelvinM,BoggsJ,DengY,HoeflichKP,LyJ,MerchantM,OrrC,PliseE,RobargeK,MartiniJF,KasseesR,AoyamaRG,RamaiyaA,JohnstonSH.PreclinicaldispositionofGDC-0973andprospectiveandretrospectiveanalysisofhumandoseandefficacypredictions.DrugMetabDispos.2012May;40(5):919-27.doi:10.1124/dmd.111.043778.Epub2012Feb7.PubMedPMID:22315332.

6:HoeflichKP,MerchantM,OrrC,ChanJ,DenOtterD,BerryL,KasmanI,KoeppenH,RiceK,YangNY,EngstS,JohnstonS,FriedmanLS,BelvinM.IntermittentadministrationofMEKinhibitorGDC-0973plusPI3KinhibitorGDC-0941triggersrobustapoptosisandtumorgrowthinhibition.CancerRes.2012Jan1;72(1):210-9.doi:10.1158/0008-5472.CAN-11-1515.Epub2011Nov14.PubMedPMID:22084396.