抗癌药研究ppt课件.ppt

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1、抗癌药研究ppt课件 Still waters run deep.流静水深流静水深,人静心深人静心深 Where there is life,there is hope。有生命必有希望。有生命必有希望 Outline vAnti-cancerdrugdiscoveryprocessvTheapproachtoanti-cancerdrugdiscoveryvIdentificationandvalidationoftargetvComputeraideddrugdesignvSmallMolecularsscreeningthroughHTSvMetabolicandPhysicochemic

2、alProfilingofdrugvCancerresistanceAnti-cancerdrugdiscoveryprocessvModernmolecularbiologyandgenomics/proteomicstoidentifyandvalidatenewtherapeutictargetsvCombinatorialchemistryfortheefficientgenerationofstructuraldiversityandforrapidproductionofalibraryofstructuralanaloguesbasedonanidentifiedleadcomp

3、oundandoptimization,enhancedstructuralbiologyandmolecularmodelingtechniquesforrationaldrugdesignvRobotichigh-throughputscreeningagainststructurallydiversechemicallibrariestodiscoverleaddrugsvHigh-throughputpharmacokineticsassays,theuseofsurrogateendpointstomonitorpharmacodynamicsthroughoutthediscove

4、ryanddevelopmentprocess,particularlyinvolvinggenomics(e.g.,nucleicacidmicroassays)andproteomicsThe approach to anti-cancer drug discoveryvcell-basedscreeningvTargetingthespecificmolecularlesionsCell-basedscreening1.cell-basedcytotoxicityassays:randomhigh-throughputscreeningofsyntheticcompoundsandnat

5、uralproducts,basedonanti-proliferativeeffects2.syntheticcompoundsandnaturalproductsbelongtoDNA-damaging agents with a low therapeutic index,Nottargetthemolecularlesionsresponsibleformalignanttransformation NCI:highlychemo-sensitiveP388leukemiacelllineTarget-basedscreeningforanti-cancerdrugdiscoveryv

6、Identification and validation of targetvEmerging targetsvDrug design and HTSIdentificationandvalidationoftargetvGenomicsanalytictechnology:microarrayanalysis,high-throughtRNAi,Ambion,Inc.CenixBioSciencevProteomicsanalytictechnology:affinitychromatographyandmassspectrometry vX-omicsanalytictechnology

7、Epigenomics(DNAmethylationandhistonedeacelylation),Cytomics,Metabolomics,Interatomics,BioinformomicsEmerging targetsvOncogenesandapoptosis-inhibitinggenes,mainlyencodingproteinsthatarecomponentsofsignaltransductionpathwaysthatregulateproliferation,differentiation,invasion/metastasis,angiogenesisand/

8、ortumorapoptosisorcelldeathvTargetsfacilitatingtumor-microenvironmentinteractionsandmetastasisvtheMoffittCancerCenterDrugDiscoveryProgramattheUniversityofSouthFloridavUniversityofIllinois:FoxM1InhibitorsareAnticancerDrugsthatInduceCellDeathvtargetingWntsignalingvmiRNAs,vHedgehogsignalingvtheNotchpat

9、hwayvmetabolicpathwaysvtheimmunesystemvspecificinflammatorymediatorsvTGFsignalingpathwayvmacrophagestimulatingprotein(MSP)anditsreceptorRonvRhoGTPasesignalingnetworkvtheIGFsignalingnetworkvApoptosisandcellcycle:Ras,aGTPase,Raf/Mek,Erk1/2,PI3K/Akt,p53,CDK4,CDK4activatorcyclinD1,CDK4inhibitorp16,Bcl-2

10、genesStructure-Based Drug Design&Virtual ScreeningvX-raycrystalstructuresand/orhomologymodelsvVirtualscreening(VS)technologies:computationally“dock”smallmoleculesintotheactivesitesofourmoleculartargetsvVisualizeandprobemolecularinteractionsin3Dusingadvancedcomputationalgraphicssystemstounderstandthe

11、forcesthatcontributetoenhancedbindingvHigh-SpeedAnaloging:parallelsynthesisandhigh-throughputpurificationtechniquescoupledwithcomputationalchemistryinput,enablestherapidgenerationofintelligentlydesignediterationsofnovelcompoundlibrariestoexpediteour“HTShit-to-lead”and“leadoptimization”drugdiscoveryp

12、rocessesvstronghardwareplatform,state-of-the-artsoftwaresuitesHigh-throughput Screening(HTS)vIncubatingthetargetproteinwithmixturesofupto500compoundsatatime.vSizeExclusionchromatography(SEC):seperatinghitsfromunboundcompoundsvmassspectrometry(LC-MS):identifyingthebindersvAnindustrial-scaleroboticche

13、rry-pickerretrievesordersofscreening“hits”forconfirmationtestingwithin24hoursMetabolicandPhysicochemicalProfiling vSolubilityandpermeability,howwelladrugisabsorbedvMetabolizationbysubcellularlivermicrosomesvPredictpossibledrug-druginteractions,testingtheirinhibitoryeffectoncytochromeP450enzymesvIden

14、tifythosecompoundsthathavethegreatestchanceofsucceedingasdrugsvMolecularImaging,luminescenceandfluorescenceimaging,visualizeandquantitatenon-invasivelyspecificmoleculartargets,biochemicalpathwaysandphysiologicaleffectsofnoveldrugcandidatesinvivoSuccessmolecularlytargeteddrugsvAll-trans-retinoicacidf

15、oracutepromyelocyticleukemiavimatinib(STI-571)forchronicmyelogenousleukemiatarget-based screening for anti-cancer drug discovery vShortcomings:vCannotdiscoverasmallmoleculethatrestoresproteinfunctionvPharmacologiceffectofthecompoundatacellularororganismlevelmaybeinfluencedvSolution:AgaindoingCell-ba

16、sedassays1.drugspharmacologiceffectsatthecellularlevel2.discoverynewtargetsTarget-basedandcell-basedscreeningfornewanticancerdrugsinthemoleculartargetingeraarecomplementarymethodsCancer resistancevCancerstemcellsareindeedmoreresistanttotherapythanothercancercellsandmightbethereasonwhyconventionalche

17、motherapy,whilereducingtumorsize,doesnotresultinlong-termcuresvAnalyzedthecancerstemcellsintenpatient-derivedtumorsimplantedinlaboratorymiceandfoundthatDR-5isenrichedincancerstemcellscomparedtonon-stemcelltumorpopulations.vRajeshKumarN.V.,Ph.D.,afacultymemberattheSidneyKimmelComprehensiveCancerCente

18、ratJohnsHopkinsUniversity:tigatuzumab,anovelhumanizeddeathreceptor-5(DR-5)agonistantibody,alongwithgemcitabine,mayresultinreducingpancreaticcancerstemcellstoachievetumorremissionandpreventtumorrecurrence.CompanyvVioQuestPharmaceuticals,Inc.vTigrisPharmaceuticals,Inc.vMitoCheckConsortium:systematicallysilencingeachgeneThanksforYourAttention