LC Labs/L5814 Linsitinib, Free Base, >99%/L5814/100 mg

• Linsitinib,alsoknownasOSI-906,isanovel,potentsmall-moleculedualinsulin-likegrowthfactor-1receptor(IGF-1R)/insulinreceptor(IR)kinaseinhibitor.
• AsofAugust18,2016,wenotethatanothervendor,Chemietek,isofferingabatchoflinsitinibthatisneitherthepurefreebasenorthepureHClsalt;ithasonly0.4equivalentofHCl.
• LinsitinibinhibitedIGF-1RandIRkinaseswithIC50valuesof35nMand75nM,respectively.LinsitinibpotentlyandselectivelyblockedautophosphorylationofbothhumanIGF-1RandIR,inhibitedtheproliferationofavarietyoftumorcelllinesinvitro,anddisplayedrobustinvivoanti-tumorefficacyinanIGF-1R-drivenxenograftmodelwhenadministeredorally.Mulvihill,M.J.,etal."DiscoveryofOSI-906:aselectiveandorallyefficaciousdualinhibitoroftheIGF-1receptorandinsulinreceptor."FutureMed.Chem.1:1153-1171(2009).
• LinsitinibshowedsuperiorefficacycomparedwithMAB391,aselectiveanti-IGF-1Rantibody,inhumantumorxenograftmodelsinwhichbothIGF-1RandIRwerephosphorylated.Buck,E.,etal."Compensatoryinsulinreceptor(IR)activationoninhibitionofinsulin-likegrowthfactor-1receptor(IGF-1R):rationaleforcotargetingIGF-1RandIRincancer."Mol.CancerTher.9:2652-2664(2010).
• Followingasingledoseoflinsitinib,18FDG-PETwasshowntoserveasarapid,noninvasivepharmacodynamicbioMarkerofIGF-1R/IRinhibition.McKinley,E.T.,etal."18FDG-PETpredictspharmacodynamicresponsetoOSI-906,adualIGF-1R/IRinhibitor,inpreclinicalmousemodelsoflungcancer."Clin.CancerRes.17:3332-3340(2011).
• IGF-1wasshowntobeoverexpressedinlow-gradeserousovariancarcinoma(SOC)whencomparedwithserousborderlineovariantumors(SBOTs)andhigh-gradeSOCs.Low-gradeSOCcelllinesweremoresensitivetoIGF-1stimulationandIGF-1Rinhibitionthanwerehigh-gradelines.Therefore,theIGF-1pathwayisapotentialtherapeutictargetinlow-gradeSOC.King,E.R.,etal."Theinsulin-likegrowthfactor1pathwayisapotentialtherapeutictargetforlow-gradeserousovariancarcinoma."Gynecol.Oncol.123:13-18(2011).
• LinsitinibblockedIGF-1signalinginLCC6xenografttumorsinvivo.Whengivenonceaweek,combinedadministrationsimultaneouslyofOSI-906anddoxorubicinsignificantlyimprovedtheanti-tumoreffectofdoxorubicin.ZengX.,etal."EnhancementofdoxorubicincytotoxicityofhumancancercellsbytyrosinekinaseinhibitionofinsulinreceptorandtypeIIGFreceptor."BreastCancerRes.Treat.133:117-126(2012).
• TherapeutictargetingofbothIRandIGF-1RbylinsitinibwasshowntobemoreeffectivethantargetingIGF-1RalonebyMAB391inabrogatingresistancetoendocrinetherapyinbreastcancer.Fox,E.M.,etal."Akinome-widescreenidentifiestheinsulin/IGF-1receptorpathwayasamechanismofescapefromhormonedependenceinbreastcancer."CancerRes.71:6773-6784(2011).
• Epithelial-mesenchymaltransition(EMT)wasdemonstratedtopredicthepatocellularcarcinomacellsensitivitytolinsitinib,astheepithelialphenotypewasstronglyassociatedwithexpressionofIGF-2andIR,andactivationofIGF-1RandIR.InductionofEMTbyTGFβreducedsensitivitytolinsitinib.Zhao,H.,etal."Epithelial-mesenchymaltransitionpredictssensitivitytothedualIGF-1R/IRinhibitorOSI-906inhepatocellularcarcinomacelllines."Mol.CancerTher.11:503-513(2012)
• Soldforlaboratoryormanufacturingpurposesonly;notforhuman,veterinary,food,orhouseholduse.
• ThisproductisofferedforR&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.421.49
C26H23N5O
[867160-71-2]

Storage

Storeatorbelow-20ºC

Solubility

SolubleinDMSOat50mg/mL;solubleinethanolat3mg/mLwithwarming;verypoorlysolubleinwater;maximumsolubilityinplainwaterisestimatedtobeabout2-5µM;buffers,serum,orotheradditivesmayincreaseordecreasetheaqueoussolubility

Disposal

A