Bruton酪氨酸激酶BTK及其抑制剂的研究进展-黄菲

JournalofChinaPharmaceuticalUniversity2014456617－624BrutonBTK121111*12111982100088BrutonBTKBBCR。BTKibrutinib。BTKBTK。BrutonR914A1000－5048201406－0617－08doi10．11665/j．issn．1000－5048．20140602ProgressofBruton'styrosinekinase(BTK)anditsinhibitorsHUANGFei1，ZHUHaijing2，ZHOUXiang1，LUTao1，JIAOYu1，TANGWeifang1*1DivisionofOrganicChemistry，ChinaPharmaceuticalUniversity，Nanjing211198;2TheSecondArtilleryGeneralHospitalofChinesePeople'sLiberationArmy，Beijing100088，ChinaAbstractBruton'styrosinekinase(BTK)，acrucialterminalkinaseenzymeintheB-cellantigenreceptor(BCR)signalingpathway，hasemergedasanattractivetargetfortherapeuticinterventioninhumanmalignanciesandautoimmunedisorders.AnumberofBTKinhibitorshaveprogressedthroughadvancedpreclinicaldevelop-menttoclinicaltrials.Amongthem，ibrutinib(PCI-32765，brandname:Imbruvica)demonstratedhighclinicalactivityinB-cellmalignancies，especiallyinpatientswithchroniclymphocyticleukemia(CLL)，mantlecelllym-phoma(MCL)，andwasrecentlyapprovedbytheU.S.FoodandDrugAdministration.Inthispaper，thestructureandfunctionofBTKarereviewed;preclinicalandclinicaldevelopmentofibrutinibandothernovelBTKinhibi-torsaresummarized.KeywordsBruton'styrosinekinase(BTK);smallmolecularinhibitor;ibrutinib;malignancyThisstudywassupportedbytheNationalNaturalScienceFoundationforYouth(No．81102318/H3001)andtheFundamentalResearchFundsfortheCentralUniversities(No.JKPZ2013002)TBB。BrutonBTKB、。BBBTK。BTKBBCRB、B。ibrutinibBTKB。BTKBTK。1BTKBTKATKagammaglobulinemiatyrosinekinaseBPKBcellprogenitorkinase716*2014-10-13*[e-mail]．81102318/H3001No.JKPZ2013002JournalofChinaPharmaceuticalUniversity45Tec。TecSrc2BTK、BMXetk、ITK、TECTXKRLK。BTK1993X-X-linkedagammaglobulinemiaXLA1－2。B3。BTK5PHPleckstrinhomologyTHTecho-mologySH3Srchomology3SH2Srchomology2SH1Srchomology141。PHBAP-135/TFII-IPIN1、IBTK5－6BTK2PIP37。THPH80。THBTKZn、PKC-β8－9。SH1、ATP、10。BTKSH1SH2SH311－12。SHBTKNLSNES13。1BTKBTK、B、。BTK、、、、14－17。BTKBTK2。PI3KPI3KPIP22PIP37。PIP3BTKPHBTKBTKTyr-551SykLyn18。BTKTyr-22312。BTKSH2BLNK/SLP65C-γ2PLC-γ219MEK/ERK、p38MAPK、NK/SAPK14－1520－22。BTKBAP-135/TFII-I、NFκB、ARID3A、STAT32BTKNFATBTK16182123。BTK13。BTKB8166BrutonBTK。BTKB、415B24－26。BTKCLL27BCR-BTKBDLBCLB28。BTK29、ALL30、CML31。BTK。2BTKBTK32－34。IbrutinibFDAMCLCLL。GDC-0834HM-71224、CC-292ONO-40591。1BTKBTKIC50/nmol/LIbrutinib0.5CLL、MCL、WM、ABC-DLBCL、MMPharmacyclicsJohnson＆JohnsonGDC-08345.9ⅠGenentechCGIPharmaceuticalsRN-4864.0ⅡONO-40592.2ⅠCLLOnoCGI-14761.9CC-2920.5ⅠCLL/BCelgeneLFM-A1317200BParkerHughesInstitute2.12.1.1IbrutinibPCI-32765ImbruvicaIbrutinibPharmacyclicsJohnson＆JohnsonBTK320131120142FDAMCLCLL。3Ibrutinib2.1.2IbrutinibIbrutinibBTKBTKIC500.5nmol/L35。BTKCys-48136。BTKTyr-223BTK35。Ibrutinibcaspase-3CLL37。IbrutinibDNA38TLR37。IbrutinibCCL3CCL4CLL38。IbrutinibPh+/BCR-ABL1B-ALL39。CLLIbrutinib25mg/kg38。HonigbergMRL-FaslprIbrutinibBTK35。2.1.3IbrutinibⅠ56CLLMCLMZLDLBCLWM40。1.252.558.312.5mg/kg28d7d35d。8.3mg/kg560mg。565DLTsIbrutinib。、、、、。、。CLLIbrutinib。60%MClCLL78%79%。1013.640。Ⅰ916JournalofChinaPharmaceuticalUniversity45Ⅱ。Wang41111Ibrutinib。560mg28d。15.368%21%47%17.513.9。Ibrutinib。20132IbrutinibFDA“”。IbrutinibⅠCLLCLLⅠb/Ⅱ。Byrd42Ibrutinib85/CLL/SLLIbrutinib420mg840mg。Ibrutinib1～2、、。840mg420mg12%vs4%。71%7d。4。2675%83%。3165CLL16.671%10%IbrutinibCLL43－44。Fowler45Ibrutinib55%13.4、。Wilson46Ibrutinib70DLBCL560mg。BABC41%GCB5%。ABC9.7GCB3.35。2.1.4IbrutinibVij47IbrutinibACY1215HDAC63。Sahakian48Ibrutinib、CLL85%。BurgerIbrutinibCLL93%49。Blum50Ibrutinib、。Ibrutinib、、CLLⅢIbrutinibCLLⅠb/Ⅱ51。IbrutinibCLL。2.2BTK2.2.1GDC-0834GDC-08344BTKBTKIC505.9nmol/L。BCRCD40B。。GDC-083452。GDC-083430～100mg/kg52。GDC-0834ⅠGDC-083453。GDC-0834。2.2.2RN-486RN-4864BTKIC50=4nmol/L。RN-486BBCRCD69。RN-486FcR-TNF-αFcεR-54。RN-48654。RN-486ⅠⅢ。RN-486IgGanti-dsDNABCRCD69SLE55。0266BrutonBTK4GDC-0834RN-4862.2.3ONO-4059ONO-4059BTKBTKIC502.2nmol/L。ONO-4059BTKBCRB。ONO-4059IL-6IL-8TNFα56。ONO-4059ⅠCLL/NHL。2.2.4CGI-1746CGI-17465ATPBTKCGI-1746BTK。BTKSH357。BCR-BFcγRIIITNFα、IL-1βIL-6。CGI-174657。2.2.5CC-292CC-2925BTK。CC-292BTKBTKIC50＜0.5nmol/L58。CC-2925659。CC-29231030mg/kgCC-292。2mg/kg20～30min1.9h。BTKCC-29258。CC-29286CLLB-NHL125～1000mg/d60。、、。3、。CC-292B。2.2.6LFM-A13LFM-A135BTK/PLK、、61。LFM-A13leflunomideBTKIC50=17.2μmol/L62。BTKB18.2NALM-6BBTK。LFM-A13Ph+ALL-1NALM-6B-ALL62。10～80mg/kgLFM-A1361。LFM-A13BTK。LFM-A1363。LFM-A13B。5CGI-1746CC-292LFM-A13126JournalofChinaPharmaceuticalUniversity453IbrutinibFDAMCLCLL。GDC-0834、HM-71224、CC-292ONO-4059。BTKB“”50－52。BTK、。BTK。-2KDRPI3K-δidelalisibBTKCC-292PI3K-δBTK。。1TsukadaSSaffranDCRawlingsDJetal．DeficientexpressionofaBcellcytoplasmictyrosinekinaseinhumanX-linkedagamma-globulinemiaJ．Cell1993722279－290.2VetrieDVorechovskyISiderasPetal．ThegeneinvolvedinX-linkedagammaglobulinaemiaisamemberofthesrcfamilyofpro-tein-tyrosinekinasesJ．Nature19933616409226－233.3deWeersMVerschurenMCKraakmanMEetal．TheBruton'styrosinekinasegeneisexpressedthroughoutBcelldifferentia-tionfromearlyprecursorBcellstagesprecedingimmunoglobulingenerearrangementuptomatureBcellstagesJ．EurJImmu-nol199323123109－3114.4KawakamiYKitauraJHataDetal．FunctionsofBruton'styro-sinekin