酪氨酸激酶抑制剂类新药的研发现状

ChineseJournalofNewDrugs2011201716612011201730973889。[e-mail]。。[e-mail]。··12121212100191。119。、。、、。。BCR-ABLEGFRVEG-FRPDGFRR969．1A1003－3734201117－1661－06CurrentstatusofresearchanddevelopmentofnewtyrosinekinaseinhibitorsZHOUBing-ying12ANChun-na12PUXiao-ping121StateKeyLaboratoryofNaturalandBiomimeticDrugs2DepartmentofMolecularandCellularPharmacologySchoolofPharmaceuticalSciencesPekingUniversityBeijing100191ChinaAbstractProteinkinasesareimportantinthepathogenesesanddevelopmentofvariousdiseasesespe-ciallytumor．KinaseinhibitorstargetingproteinkinasesgarnertheattentionofdrugresearchanddevelopmentR＆Dinrecentyears．Currently11small-moleculekinaseinhibitorshavebeenapprovedamongthem9arethetyrosinekinaseinhibitors．Kinaseinhibitorshavehighselectivityandminimalsideeffects．ApproveddrugshaveshowntheirsuperiorityovertraditionaltreatmentsinchronicmyeloidleukemiaCMLnon-smallcelllungcancerNSCLCandrenalcellcarcinomaRCCsomeofthemalreadyhavebecomethefirst-linetreatmentoftumors．InthepresentpaperthecurrentstatusofthenewdrugR＆Dofsmall-moleculetyrosinekinaseinhibitorswasre-viewed．KeywordskinaseinhibitornewdrugBCR-ABLepidermalgrowthfactorreceptorEGFRvascularendothelialgrowthfactorreceptorVEGFRplatelet-derivedgrowthfactorreceptorPDGFRATP。。。。。50%。1chronicmyeloidleukemiachronicChineseJournalofNewDrugs20112017166220112017myelogenousleukemiaCML、non-smallcelllungcancerNSCLCrenalcellcarcinomaRCC。FoodandDrugAdministrationFDA119。。。、。、。。1CMLBCR-ABLCML922breakpointclusterregionBCR-Abelsonleukemiavi-rusABLPhiladelphiaPhBCR-ABL。BCR-ABLCMLCML。1．1CMLNovartisimatinibGleevec2001FDACMLCML2。BCR-ABLATPCML。α70%completecytogeneticremissionCcyR。98%CYP3A4N-。2stem-cellfactorreceptorKITplatelet-derivedgrowthfactorre-ceptorPDGFR。BCR-ABLKITPDGFRIC506585839nmol·L－1。2008FDA。①。②。1．2CMLBCR-ABLnilotinib、dasatinibbafetinib。CcyRBCR-ABL。Tasigna2007FDAPh+CMLCcyR87%。BCR-ABLBCR-ABLKITPDGFRIC502515853nmol·L－13。Bristol-MyersSquibbSprycelBCR-ABLSrc2006BCR-ABL23004。Ph+CMLPh+a-cutelymphoblasticleukemiaPh+ALL。CytRxBCR-ABLLynSrcCML、、5。25～3510。1．3CMLBCR-ABL25%T315I。CMLT315I。BCR-ABL。MK-0457aurorakinaseAK/T315IBCR-ABLChineseJournalofNewDrugs20112017166320112017。MK-0457T315IMK-04573T315I1。danusertibBCR-ABLIC50=25nmol·L－16。PonatinibBCR-ABLBCR-ABLIC50=0．37nmol·L－1T315IIC50=2．0nmol·L－1。Ⅰ66%CML100%T315I。bosutinibBCR-ABLSrc。1。1CMLBCR-ABLMK-0457MerckAK/BCR-ABLT315IⅠdanusertibNervianoMedicalSciencesAK/BCR-ABLT315IⅡPonatinibAriadBCR-ABLT315IⅡbosutinibWyethBCR-ABLT315I/SrcⅢXL-228ExelixisBCR-ABLT315I/SrcⅠDCC-2036DecipheraBCR-ABLT315I/SrcⅠ2NSCLCEGFR120。75%～85%。NSCLC。71。1EGFRepidermalgrowthfactorre-ceptorEGFR。EGFR、。40%～80%NSCLCEGFREGFRNSCLC。2．1NSCLCge-fitinibIressaAstraZenecaEGFR1EGFR2003FDA8。EGFRIC50=23nmol·L－1。9%～19%40%NSCLC。2EGFR2004erlotinibTacervaOSI98．9%NSCLC。2．2NSCLClapatinibTykerbGlaxo-SmithKlineEGFR/HER22humanepidermalgrowthfactor22007FDAcapecitabine、HER210。NSCLCⅡ。ChineseJournalofNewDrugs20112017166420112017vandetanibZactimaTM2vascularendothelialgrowthfactorreceptor2VEGFR-2、EGFRglialcell-linederivedneurotrophicfactorreceptorRET11。NSCLCNSCLC。NSCLC2。2NSCLCEGFRlapatinibGlaxoSmithKlineEGFR/HER2ⅡvandetanibAstraZenecaVEGFR-2/EGFR/RETpelitinibWyethEGFRneratinibWyethEGFR/HER2canertinibPfizerEGFRⅡPF-00299804PfizerEGFRⅢXL647ExelixisEGFR/HER2/VEGFRafatinibBoehringerIngelheimEGFR/HER2/VEGFRⅡBCR-ABLEGFRNSCLC。。EGFR、、。3RCCVEGFRPDGFR85%80%。RCC10%RCC5。RCC。VEGFRPDGFRRCC。RCC、vonHippel-LindauVHL。VHLvascularendothelialgrowthfac-torVEGFplatelet-derivedgrowthfactorPDGF。VEGFRPDGFRVEGFPDGFRCC。5RCC3。3．1RCCsorafenibNexavar2005RAF/VEGFR/PDGFRBayerhepatocellularcarcino-maHCCRCC1FDARCC112。CYP3A4UGT1A9N-。Ⅱ90%35%。sunitinibSutentSU012662VEGFRPDGFRKIT。2006FDARCC41～86h。。KIT。3．2RCC2009pazopanibVotrientVEGFR/PDGFRKITRCC13。CYP3A4。。tivozanibAVEO、VEGFR。3。ChineseJournalofNewDrugs201120171665201120173RCCVEGFR/PDGFRtivozanibAVEOVEGFRⅢaxitinibPfizerVEGFR/PDGFR/KITⅢcediranibAstraZenecaVEGFRintedanibBoehringerIngelheimVEGFR/FGFRa/PDGFRⅡGSK1363089GlaxoSmithKlineMET/VEGFR-2ⅡlifatinibAbbottVEGF/PDGFdovitinibNovartisVEGFR/FGFR/PDGFR/KITⅡbrivanibBristol-MyersSquibbVEGFR-2/FGFRBIBF1120BoehringerIngelheimVEGFR/PDGFR/FGFRahand-footsyndromeHFS。4。。p38p38mitogen-activatedproteinkinasep38MAPKGSK610677COPDⅠSB-681323COPD、、、、LosmapimodCOPDVX-702Ⅱ。/mammaliantargetofrapamycinmTOR、AK、cyclin-de-pendentkinaseCDKToriselAfinitor。cetuximabpanitumumabtrastuzumabbevaci-zumab。、。。。ATPbindingcassettetransporterABC-transporter。。2ABCP-gpBCRP。ABC。Elacridar14。。BCR-ABLT315I。semaxanibSU6668。。。5。。。11。。。ChineseJournalofNewDrugs20112017166620112017。1ARORAASCHOLAREM．RoleoftyrosinekinaseinhibitorsincancertherapyJ．JPharmacolExpTher20053153971－979．2BRECCIAMEFFICACEFALIMENAG．ImatinibtreatmentinchronicmyelogenousleukemiaWhathavewelearnedsofarJ．CancerLett20113002115－121．3DEININGERMW．NilotinibJ．ClinCancerRes200814134027－4031．4SHAYANIS．Dasatinibamultikinaseinhibitortherapysafe-tyandappropriatemanagementofadverseeventsJ．TherDrugMonit2010326680－687．5SANTOSFPKANTARJIANHCORTESJetal．BafetinibadualBcr-Abl/Lyntyrosinekinasein