LC Labs/F4185 Foretinib, Free Base, >99%/F4185/200 mg

• Foretinib,alsoknownasEXEL-2880,XL880,andGSK1363089,isasmall-moleculeinhibitorofthehepatocytegrowthfactor(HGF)andvascularendothelialgrowthfactor(VEGF)receptortyrosinekinasefamilies.
• Foretinibinhibitedreceptortyrosinekinases(RTKs)invitrowithIC50valuesof0.4nMforMetand3nMforRon.ItinhibitedcellularMetwithIC50valuesof23nMinPC-3prostatecellsand21nMinmurineB16F10melanomacells.Italsoreducedtumorcellmigration,invasion,andendothelialtubuleformation.Foretinibhadcytotoxicactivitiesagainstabroadpanelofcelllines.ItalsoblockedlungmetastasisaftertheimplantationofB16F10solidtumorsinmice.Qian,F.,etal."Inhibitionoftumorcellgrowth,invasion,andmetastasisbyEXEL-2880(XL880,GSK1363089),anovelinhibitorofHGFandVEGFreceptortyrosinekinases."CancerRes.69:8009-8016(2009).
• MET-amplifiedtumorlineswithHER1orHER2amplificationaremoresensitivetothecombinationofforetinibwithlapatiniborerlotinib.MET-overexpressingtumorcelllineswithHER1orHER2amplificationarelesssensitivetolapatiniborerlotinibinthepresenceofHGF.ForetinibcanreversetheeffectofHGFonlapatiniborerlotinibsensitivityinthesecells.Liu,L.,etal."SynergisticeffectsofforetinibwithHER-targetedagentsinMETandHER1-orHER2-coactivatedtumorcells."Mol.CancerTher.10:518-530(2011).
• Foretinibinhibitstumorigenesisandblocksinvasivetumorgrowthindifferentmodelsofovariancancerbyaffectingseveralcriticaltumorfunctionsincludinginducinganoikis(anchorage-dependentprogrammedcelldeath)andinhibiting(1)c-Metactivationanddownstreamsignaling,(2)ovariancancercelladhesion,(3)migrationandinvasion,and(4)proliferation.Zillhardt,M.,etal."Foretinib(GSK1363089),anorallyavailablemultikinaseinhibitorofc-MetandVEGFR-2,blocksproliferation,inducesanoikis,andimpairsovariancancermetastasis."Clin.CancerRes.17:4042-4051(2011)
• ForetinibpotentlyblockmultipleRTKs,includingVEGFreceptorandthereceptorofHGFc-Met.Inhibitionofc-MetandfunctionallyrelatedkinasesintensifiestheeffectsofVEGFreceptorblockade,whichleadstoregressionoftumorvasculature.You,W.K.,etal."VEGFandc-Metblockadeamplifyangiogenesisinhibitioninpancreaticisletcancer."CancerRes.71:4758-4768(2011).
• ForetinibcausedmitoticcatastropheinchronicmyelogenousleukemiacellsandothercelllinesbyJNK-dependentinhibitionofPlk1expressionandinducedapoptosisviaacaspase2-mediatedmechanism.Dufies,M.,etal."MechanismofactionofthemultikinaseinhibitorForetinib."CellCycle10:4138-4148(2011).
• ForetinibhadcytotoxiceffectsagainstgastriccancercellsharboringMETandFGFR2amplification.Itexerteditscytotoxiceffectsbyblockinginter-RTKsignalingnetworkswithMETorFGFR2attheircenter.Kataoka,Y.,etal."Foretinib(GSK1363089),amulti-kinaseinhibitorofMETandVEGFRs,inhibitsgrowthofgastriccancercelllinesbyblockinginter-receptortyrosinekinasenetworks."Invest.NewDrugs30:1352-1360(2012).
• Foretinibwasshowntohavesignificantantitumoractivitiesinpatient-derivedhepatocellularcarcinomaxenograftmodels.Huynh,H.,etal."Foretinibdemonstratesanti-tumoractivityandimprovesoverallsurvivalinpreclinicalmodelsofhepatocellularcarcinoma."Angiogenesis15:59-70(2012).
• AnotherCASnumberpreviouslyassignedtoforetinibfreebase,namely937176-80-2,hasbeendeletedbyCASandisnolongerinuse.
• Soldforlaboratoryormanufacturingpurposesonly;notforhuman,veterinary,food,orhouseholduse.
• hisproductisofferedforR&Duseinaccordancewith(i)35USC271(e)+A13(1)intheU.S.;(ii)Section69.1ofJapanesePatentLawinJapan;(iii)Section11,No.2oftheGermanPatentActof1981inGermany;(iv)Section60,Paragraph5boftheU.K.PatentsActof1977intheU.K.;(v)Sections55.2(1)and55.2(6)andothercommonlawexemptionsofCanadianpatentlaw;(vi)Section68BofthePatentsActof1953inNewZealandtogetherwiththeamendmentofsamebytheStatutesAmendmentBillof2002;(vii)suchrelatedlegislationand/orcaselawasmaybeorbecomeapplicableintheaforementionedcountries;and(viii)suchsimilarlawsandrulesasmayapplyinvariousothercountries.
• Notavailableinsomecountries;notavailabletosomeinstitutions;notavailableforsomeuses.

M.W.632.65
C34H34F2N4O6
[849217-64-7]

Storage

Storeatorbelow-20ºC

Solubility

SolubleinDMSOat150mg/mL;solubleinethanolat5mg/mLwithwarming;verypoorlysolubleinwater;maximumsolubilityinplainwaterisestimatedtobeabout5-10µM;buffers,serum,orotheradditivesmayincreaseordecreasetheaqueoussolubility

Disposal

A