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1、5DISCOVERYOFMOTESANIBAndrewS.TaskerandVinodF.Patel5.1.INTRODUCTIONPathologicalangiogenesisisassociatedwithavarietyofdiseasestates,includ-ingpsoriasis(Detmar,2000),diabeticretinopathy(Adamisetal.,1993),rheu-matoidarthritis(Giatromanolakietal.,2001),andcancer(Carme
2、lietandJain,2000).Incancer,tumordevelopmentbeyondacertainsizegivesrisetoahypoxicstateaspassivediffusionfailstokeeppacewiththetumor’sgrowingdemandforoxygen.Inresponse,thetumorinitiatesanangiogenicprogramtranscribingamultitudeofcytokines,oneofwhichisthevascularendo
3、thelialgrowthfactororVEGF,whosemitogenicsignalinginendothelialcellsiscon-veyedthroughthereceptortyrosinekinaseVEGFR2(Dvorak,2002).AnincreasingbodyofevidenceindicatesthattheexpressionandactionofVEGFiscriticalfortumorangiogenesis;anti-ligand(Hurwitzetal.,2004)andan
4、ti-receptor(Witteetal.,1998)antibodies,inadditiontochemicalinhibitors(Hurwitzetal.,2005;Ryanetal.,2005;Strumbergetal.,2005;Motzeretal.,2006;Drevsetal.,2007)ofthekinaseactivityhavebeenshowntoablateneovascularizationinpreclinicalmodelsofangiogenesisandintumorxeno-g
5、rafts,andhaveenteredclinicaltrials.Bevacizumab,arecombinanthumanizedmonoclonalantibodydirectedagainstVEGF,isapproved(Cohenetal.,2007)forfirstorsecondlinetreatmentofpatientswithmetastaticcarcinomaofthecolonorrectumandforpatientswithadvancednonsquamousnon-small-cell
6、lungcancer(Sandleretal.,2006).Sunitinibisapproved(Goodmanetal.,2007)forthetreatmentofrenalcellcarcinoma(RCC)andimatinib-resistantgas-trointestinalstromaltumors(GIST).SorafenibisapprovedforRCCandhepatocellularcarcinoma(HCC)(Zhu,2008).BytargetingthegeneticallyKinas
7、eInhibitorDrugs.EditedbyRongshiLiandJeffreyA.StaffordCopyright©2009JohnWiley&Sons,Inc.113114DISCOVERYOFMOTESANIBstablevascularsystemwhereinmutationsrarelyoccur,therapy-inducedresis-tanceisexpectedtobeminimal.VEGF,however,isknowntomediateendothelium-dependentvasor
8、elaxationinasignalingeventalsodriventhroughVEGFR2(Lietal.,2002);thusinhibitionofthissignalingpathwaymaypoten-tiallyleadtoanon-mechanismhypertensivesideeffect.W
