抗癌药研究.ppt

Anti-cancerDrugDiscoveryandDevelopment,Outline,Anti-cancerdrugdiscoveryprocessTheapproachtoanti-cancerdrugdiscoveryIdentificationandvalidationoftargetComputeraideddrugdesignSmallMolecularsscreeningthroughHTSMetabolicandPhysicochemicalProfilingofdrugCancerresistance,Anti-cancerdrugdiscoveryprocess,Modernmolecularbiologyandgenomics/proteomicstoidentifyandvalidatenewtherapeutictargetsCombinatorialchemistryfortheefficientgenerationofstructuraldiversityandforrapidproductionofalibraryofstructuralanaloguesbasedonanidentifiedleadcompoundandoptimization,enhancedstructuralbiologyandmolecularmodelingtechniquesforrationaldrugdesignRobotichigh-throughputscreeningagainststructurallydiversechemicallibrariestodiscoverleaddrugsHigh-throughputpharmacokineticsassays,theuseofsurrogateendpointstomonitorpharmacodynamicsthroughoutthediscoveryanddevelopmentprocess,particularlyinvolvinggenomics(e.g.,nucleicacidmicroassays)andproteomics,Theapproachtoanti-cancerdrugdiscovery,cell-basedscreeningTargetingthespecificmolecularlesions,Cell-basedscreening,1.cell-basedcytotoxicityassays:randomhigh-throughputscreeningofsyntheticcompoundsandnaturalproducts,basedonanti-proliferativeeffects2.syntheticcompoundsandnaturalproductsbelongtoDNA-damagingagentswithalowtherapeuticindex,NottargetthemolecularlesionsresponsibleformalignanttransformationNCI:highlychemo-sensitiveP388leukemiacellline,Target-basedscreeningforanti-cancerdrugdiscovery,IdentificationandvalidationoftargetEmergingtargetsDrugdesignandHTS,Identificationandvalidationoftarget,Genomicsanalytictechnology:microarrayanalysis,high-throughtRNAi,Ambion,Inc.CenixBioScienceProteomicsanalytictechnology:affinitychromatographyandmassspectrometryX-omicsanalytictechnologyEpigenomics(DNAmethylationandhistonedeacelylation),Cytomics,Metabolomics,Interatomics,Bioinformomics,Emergingtargets,Oncogenesandapoptosis-inhibitinggenes,mainlyencodingproteinsthatarecomponentsofsignaltransductionpathwaysthatregulateproliferation,differentiation,invasion/metastasis,angiogenesisand/ortumorapoptosisorcelldeathTargetsfacilitatingtumor-microenvironmentinteractionsandmetastasistheMoffittCancerCenterDrugDiscoveryProgramattheUniversityofSouthFloridaUniversityofIllinois:FoxM1InhibitorsareAnticancerDrugsthatInduceCellDeath,targetingWntsignalingmiRNAs,HedgehogsignalingtheNotchpathwaymetabolicpathwaystheimmunesystemspecificinflammatorymediatorsTGFsignalingpathwaymacrophagestimulatingprotein(MSP)anditsreceptorRonRhoGTPasesignalingnetworktheIGFsignalingnetworkApoptosisandcellcycle:Ras,aGTPase,Raf/Mek,Erk1/2,PI3K/Akt,p53,CDK4,CDK4activatorcyclinD1,CDK4inhibitorp16,Bcl-2genes,Structure-BasedDrugDesign&VirtualScreening,X-raycrystalstructuresand/orhomologymodelsVirtualscreening(VS)technologies:computationally“dock”smallmoleculesintotheactivesitesofourmoleculartargetsVisualizeandprobemolecularinteractionsin3Dusingadvancedcomputationalgraphicssystemstounderstandtheforcesthatcontributetoenhancedbinding,High-SpeedAnaloging:parallelsynthesisandhigh-throughputpurificationtechniquescoupledwithcomputationalchemistryinput,enablestherapidgenerationofintelligentlydesignediterationsofnovelcompoundlibrariestoexpediteour“HTShit-to-lead”and“leadoptimization”drugdiscoveryprocessesstronghardwareplatform,state-of-the-artsoftwaresuites,High-throughputScreening(HTS),Incubatingthetargetproteinwithmixturesofupto500compoundsatatime.SizeExclusionchromatography(SEC):seperatinghitsfromunboundcompoundsmassspectrometry(LC-MS):identifyingthebindersAnindustrial-scaleroboticcherry-pickerretrievesordersofscreening“hits”forconfirmationtestingwithin24hours,MetabolicandPhysicochemicalProfiling,Solubilityandpermeability,howwelladrugisabsorbedMetabolizationbysubcellularlivermicrosomesPredictpossibledrug-druginteractions,testingtheirinhibitoryeffectoncytochromeP450enzymesIdentifythosecompoundsthathavethegreatestchanceofsucceedingasdrugsMolecularImaging,luminescenceandfluorescenceimaging,visualizeandquantitatenon-invasivelyspecificmoleculartargets,biochemicalpathwaysandphysiologicaleffectsofnoveldrugcandidatesinvivo,Successmolecularlytargeteddrugs,All-trans-retinoicacidforacutepromyelocyticleukemiaimatinib(STI-571)forchronicmyelogenousleukemia,target-basedscreeningforanti-cancerdrugdiscovery,Shortcomings:CannotdiscoverasmallmoleculethatrestoresproteinfunctionPharmacologiceffectofthecompoundatacellularororganismlevelmaybeinfluencedSolution:AgaindoingCell-basedassays1.drugspharmacologiceffectsatthecellularlevel2.discoverynewtargetsTarget-basedandcell-basedscreeningfornewanticancerdrugsinthemoleculartargetingeraarecomplementarymethods,Cancerresistance,Cancerstemcellsareindeedmoreresistanttotherapythanothercancercellsandmightbethereasonwhyconventionalchemotherapy,whilereducingtumorsize,doesnotresultinlong-termcuresAnalyzedthecancerstemcellsintenpatient-derivedtumorsimplantedinlaboratorymiceandfoundthatDR-5isenrichedincancerstemcellscomparedtonon-stemcelltumorpopulations.,RajeshKumarN.V.,Ph.D.,afacultymemberattheSidneyKimmelComprehensiveCancerCenteratJohnsHopkinsUniversity:tigatuzumab,anovelhumanizeddeathreceptor-5(DR-5)ago