屆全國醫(yī)藥經(jīng)濟(jì)信息發(fā)布會新藥研發(fā)中的結(jié)構(gòu)優(yōu)化策略

中科院廣州生物醫(yī)藥與健康研究院呼吸病國家重點實驗室張健存jiancunzhang@2011.11.11新藥研發(fā)中的結(jié)構(gòu)優(yōu)化策略醫(yī)藥市場

國際：

年代銷售額（億美元）

19972,20020014,30020045,00020107,000

國內(nèi)：年代銷售額（億人民幣）

19961,10020012,50020043,40020106,000

預(yù)計：未來幾年全球醫(yī)藥市場銷售額年增長率將大于7%,我國將大于10%NumbersofDrugApprovedSince1950Naturereviewdrugdiscovery2009Totalof1222drugsapprovedincluding119biologicsAverageannualapprovalabout20Morethan4000companiesengagedindrugR&D,only261companieshaveatleastoneapproved藥物開發(fā)流程N(yùn)aturereviewdrugdiscovery,2004新藥R&D的周期ResearchLateDevelopmentEarlyDevelopmentRegulatoryassessmentCommercial-izationPre-clinicalevaluationClinicalevaluation2.9yrs1.5yrs5.7yrsUSFDA:1.0yrsEMEA:1.3yrsJapaneseMHLW:1.4yrsDuration(median)TargetdiscoveryAssaydevelopmentLeaddiscoveryLeadoptimisationFocus先到化合物的發(fā)現(xiàn)Insilicascreening(虛擬篩選）HTSscreeningofcompoundlibraries.Naturalproductslead（天然產(chǎn)物）Endogenousligandbased（天然底物）:PeptideTransitionstatemimeticEndogenousligand/substrateLiteratureleads/existingdrugmolecules（報道化合物以及已有藥物分子）LeadMoleculeDrug(NME)?藥物分子發(fā)現(xiàn)的關(guān)鍵環(huán)節(jié)先導(dǎo)化合物具有結(jié)構(gòu)專利的藥物分子先導(dǎo)化合物結(jié)構(gòu)優(yōu)化(1):PeptideBACEHCVproteaseP1CYS先導(dǎo)化合物結(jié)構(gòu)優(yōu)化(2):TSmimeticInfluenzaNeuraminidaseInhibitors（流感神經(jīng)氨酸酶抑制劑）先導(dǎo)化合物結(jié)構(gòu)優(yōu)化(3):EndogenousSubstrate（天然底物）capcitabineFast-FollowerApproach快速跟進(jìn)策策略ValidatedtargetforacertaindiseaseOptimizeownleadClearpatentMaybecome1stinclassMoreuncertaintyFollowingother’sprovenstructurallead,optimizeTimesavingNarrowerIP/MarketingcompetitionFastFollowerApproachAnalysesPros（優(yōu)勢）FastentryintoanewprojectProvenpathtosuccessCommonlypracticedinindustryCons（劣勢）IPpositionMayhavesimilarliabilitiestothecompetitorGershell,AtkinsNatRev.DrugDisc,2003,321Booth,Zemmel,ibid,2003,838FastFollowerStrategies（策略）DetailedPatentinformationawarenessandSAR（專利及構(gòu)構(gòu)效關(guān)系分分析）Leadoptimizationstartegies（結(jié)構(gòu)優(yōu)化化策略）Bio-isosterereplacementsConformationrigidityAuxophorereplacementADMETmodificationsFocusondifferentiationandimprovement:toxicity,resistancedoseconvenience,efficacyLuck!!!PharmacorphoreandAuxophore藥效基團(tuán)和和輔助基團(tuán)團(tuán)Pharmacophore:TherelevantgroupormoietyofthemoleculethatinteractwiththemoleculetargetandproducebioactivityAuxophore:Therestofthemoleculethatdoesnotdirectlyinteractwiththetarget,butmayaffectbinding;mainlyusedforADMETimprovementApplicationofAuxophoresHMG-CoAreductaseinhibitors(他汀類藥物物)ApplicationofBioisosteres等效基團(tuán)的的應(yīng)用AngiotensinIIantagonistH2(histamine)antagonistCimetidine(Tagamet)ApplicationofBioisosteresPDE-5Inhbitorssildenafil,Pfizervardenafil,GSK-BayerMoreSelectivevsPDE-6(Bluevision)Fasteron-settime我們的研究究領(lǐng)域新型抗腫瘤瘤藥物的研研究開發(fā)靶向藥物及及天然產(chǎn)物物新型抗病毒毒藥物的研研究開發(fā)流感藥物,核苷類抗病病毒藥物(肝炎和呼吸吸道病毒)原料藥產(chǎn)業(yè)業(yè)化新工藝藝的開發(fā)NovelTyrosineKinaseInhibitorsasanticanceragentsTyrosineKinaseInhibitorsasAnticancerAgentsTyrosineKinaseisaproteinfoundwithinmanytumorcellsTyrosineKinaseisresponsibleforsendingsignalstomaintainconstantproliferationTKI’sblocktheabilityoftyrosinekinasetofunction–therebylimitingcancergrowthTKI’scauserapidcancercelldeathbyshuttingdowncancercellsurvivalmechanismTumorGenotypeandTKIsTumorGenotypeandTKIs-2ApprovedKinaseDrugsGefitinib(Iressa?)Imatinib(Gleevec?)Erlotinib(Tarceva?)Sunitinib(Sutent?)Sorafenib(Nexavar?)Dasatinib(Sprycel?)Lapatinib(Tykerb?)Nilotinib(Tasigna?)Structure,TargetandIndicationsofApprovedTKIDrugs-1Structure,TargetandIndicationsofApprovedTKIDrugs-2我們抗腫瘤瘤領(lǐng)域研究究的策略Basedstructureofvalidatedscaffolds,designanddiscovernovelEGFRinhibitorsthroughtheauxophoreapproach（輔助基團(tuán)的的改造）DesignanddiscovernovelEGFR/Her2dualinhibitors（不可逆抑制制劑）DNAMembraneExtracellularIntracellularRKRKEGFR-TKIEGFR-TKI??SignallingProliferationCellsurvival(anti-apoptosis)GrowthfactorsChemotherapy/radiotherapysensitivityAngiogenesisMetastasis?R,epidermalgrowthfactorreceptorEGF/TGFαAntibody基于EGFR信號傳導(dǎo)的靶靶向藥物治療療表皮生長因子子受體(EGFR)EGFR是一種跨膜受受體在多種惡性腫腫瘤有EGFR過度表達(dá)EGFR的的過度表達(dá)可以促促進(jìn)腫瘤細(xì)胞胞增殖、血管管生成、粘附、侵襲和轉(zhuǎn)轉(zhuǎn)移，抑制腫瘤細(xì)胞胞的凋亡，導(dǎo)致腫瘤患者者存活率低，預(yù)后差，療效差，腫瘤轉(zhuǎn)移可能能性大容易引起腫瘤瘤細(xì)胞對各種種細(xì)胞毒性藥藥物的耐藥。EGFRTargetedDrugsReceptortyrosinekinasestargetingdrugs-lungcancerEGFR的活性口袋模模型ATPbindingSiteDel-1(E746-A750)andDel-2(L747-T751)occurrightaftercatalyticK745andbeforehelixC.ThisdeletionwillcertainlyinterferethesaltbridgebetweenK745andE762byeithershiftingthehelixCpositionorchangingthehelixturn.Alsointhosedeletions,thenewlyformedstructureinthisregionhasthepotentialtomakecontactwithP-loop,andthereforechangetheP-loopconformation,(P-loopisaGlyrichloopandhasextremelyhighmobility,andF723intheP-loopmakeflipwhentheloopshiftsandmakenewhydrophobicinteractions.InhibitorLys突變部位EGFRMutationIncreaseIressaSensitivity?JapanUSChina*Iressa(TKI) 27.5%10.4%~40%？mutations% 25.9%1.8%40.9%J.Clin.Oncol.,21:2237Science304:1497-1500*Qinetal,CellRes(GIBH,CAS)EGFRMutationIncreaseIressaSensitivity?苯胺的4-位上容忍較大大的取代基團(tuán)團(tuán)，而且這種種較大基團(tuán)的的存在，能夠夠提高對HER2的抑制活性利用EGFR和HER2激酶ATP結(jié)合區(qū)邊緣的的Cys773和Cys805氨基酸殘基上上巰基具有較較強(qiáng)的親核性性的特點，在在藥物分子中中引入一個Michael加成受體，使使藥物分子能能夠與激酶形形成共價鍵結(jié)結(jié)合，達(dá)到不不可逆抑制的的目的。QuinazolineSAR基于藥物分子子輔助基團(tuán)的的結(jié)構(gòu)修飾AuxophoreandSolventinteractionModificationsiteIressaOver100newanalogsmadeEGFR激酶抑制篩選選實驗以及MTT腫瘤增長抑制制細(xì)胞篩選表表明我們的部部分化合物展展現(xiàn)出比IRESSA高20倍的生物抑制制活性CompoundIDIC50nM(U87MG)IC50nM(A549)EGFRKinaseAssay（IC50）Iressa>20>2080nMZ5091.214120nMZ5461.51915nMZ580>20>2090nMZ5821.4114nMZ583>201512nMZ594>20>2020nM體外藥效人表皮樣癌A431裸小鼠移植瘤瘤的療效人表皮樣癌A431裸小鼠移植瘤瘤的療效圖人表皮樣癌A431裸小鼠移植瘤瘤的照片EGFR抑制劑小結(jié)新化合物受體體活性比易瑞瑞沙提高近20倍細(xì)胞抑制活性性有近20倍提高新化合物有很很好的體內(nèi)抑抑制活性（劑劑量調(diào)整中））新化合物有較較好的藥物代代謝及理化性性質(zhì)EGFR/Her2DualInhibitorsLapatinibisanapprovedEGFR/Her2inhibitorforbreastcancerLapatinibhasundesirablepropertiesToolargedosage1250mgdailyLimitedefficacySideeffectsDiarrheaPalmar-plantarerythrodysesthesiaNausea/vomiting,Rash,FatigueDecreasesinLVEF(possiblyduetometabolites)NovelDualKinaseInhibitors雙重抑制劑策策略DualEGFR/Her2bothreversibleandirreversibleSmallMoleculeInhibitorOvercomelapatiniblivertoxicityReducedosageoflapatinib(potencyandirreversiblemechanism)IrreversibleKinaseInhibitors現(xiàn)有不可逆駱駱氨酸激酶抑抑制劑Afatinib,EGFR/Her2inhibitorPhaseIII,Boehringer-IngelheimBreast,prostateNeratinib,EGFR/Her2inhibitorBreastcancer可逆逆和和不不可可逆逆抑抑制制劑劑可逆逆性性抑抑制制劑劑抑制制劑劑通通過過與與ATP競爭爭占占據(jù)據(jù)受受體體結(jié)結(jié)合合，，選選擇擇性性抑抑制制胞胞內(nèi)內(nèi)酪酪氨氨酸酸激激酶酶活活動動區(qū)區(qū)，，可可逆逆地地抑抑制制酶酶的的催催化化活活性性和和酪酪氨氨酸酸自自磷磷酸酸化化，，阻阻止止下下游游信信號號傳傳導(dǎo)導(dǎo)。。不可可逆逆抑抑制制劑劑抑制制劑劑通通過過與與ATP競爭爭性性地地占占據(jù)據(jù)受受體體結(jié)結(jié)合合腔腔，，并并且且與與受受體體發(fā)發(fā)生生共共價價鍵鍵合合作作用用，，不不可可逆逆地地結(jié)結(jié)合合在在受受體體上上，，從從而而產(chǎn)產(chǎn)生生不不可可逆逆地地抑抑制制不可可逆逆抑抑制制劑劑的的優(yōu)優(yōu)勢勢TraditionalKinaseInhibitorsshowonlymodestclinicalefficacydespiteexcellentbiomolecularandcellularactivitiesImpedemutationoccurance(遲緩緩基基因因變變異異)Alkylationagentshavebeenusedascytotoxics(烷基基化化腫腫瘤瘤藥藥物物)Irreversibleagentsmightbetargetedagentscytotoxicswithbettertumorcellkillingability(高活活性性的的靶靶向向藥藥物物)我們們的的研研發(fā)發(fā)策策略略Designedandsynthesized>50quinazolineandcyanoquinalinecompoundstargetingbothEGFRandHer2UtilizingEGFRC773nucleophilicityforcovalentbondingforirreversibleinhibitionReplacethemetabolicallyunstableaminophenolmoietytoreducelivertoxicityModifyingsidechainforbetterPKandpotencyEGFRInhibition(上皮皮生生長長因因子子受受體體抑抑制制)Her2InhibitionCompound193324andothersshowedcomparableHer2inhibitionpotencyanIrreversibleKinaseInhibitorLapatinibisreversibleinhibitorforEGFR.193324isanirreversibleEGFRinhibitorWZ4002isanknownIrreversibleEGFRinhibitor.MorePotentCellularActivity不可可逆逆雙雙重重抑抑制制劑劑小小結(jié)結(jié)Havegeneratedover100EGFRandHer2dualinhibitorsSomeEGFRinhibitorsdemonstratedpotentbiomolecularandcellularinhibitionactivityaswellasinvivoinhibitoryactivityCompound193324showntobeirreversibledualinhibitorPreliminaryPKstudiesshowedfavorableprofiles中國國創(chuàng)創(chuàng)新新藥藥物物研研究究的的優(yōu)優(yōu)勢勢市場場優(yōu)優(yōu)勢勢巨大大內(nèi)內(nèi)需需市市場場市場場進(jìn)進(jìn)入入門門檻檻較較底底,(non-inferiorok?)開發(fā)發(fā)優(yōu)優(yōu)勢勢充足