抗癌药研究专题知识讲座

抗癌药研究专题知识讲座抗癌药研究专题知识讲座第1页OutlineAnti-cancerdrugdiscoveryprocessTheapproachtoanti-cancerdrugdiscoveryIdentificationandvalidationoftargetComputeraideddrugdesignSmallMolecularsscreeningthroughHTSMetabolicandPhysicochemicalProfilingofdrugCancerresistance抗癌药研究专题知识讲座第2页Anti-cancerdrugdiscoveryprocessModernmolecularbiologyandgenomics/proteomicstoidentifyandvalidatenewtherapeutictargetsCombinatorialchemistryfortheefficientgenerationofstructuraldiversityandforrapidproductionofalibraryofstructuralanaloguesbasedonanidentifiedleadcompoundandoptimization,enhancedstructuralbiologyandmolecularmodelingtechniquesforrationaldrugdesignRobotichigh-throughputscreeningagainststructurallydiversechemicallibrariestodiscoverleaddrugsHigh-throughputpharmacokineticsassays,theuseofsurrogateendpointstomonitorpharmacodynamicsthroughoutthediscoveryanddevelopmentprocess,particularlyinvolvinggenomics(e.g.,nucleicacidmicroassays)andproteomics抗癌药研究专题知识讲座第3页Theapproachtoanti-cancerdrugdiscoverycell-basedscreeningTargetingthespecificmolecularlesions抗癌药研究专题知识讲座第4页Cell-basedscreening1.cell-basedcytotoxicityassays:

randomhigh-throughputscreeningofsyntheticcompoundsandnaturalproducts,basedonanti-proliferativeeffects2.syntheticcompoundsandnaturalproductsbelongto

DNA-damagingagentswithalowtherapeuticindex,NottargetthemolecularlesionsresponsibleformalignanttransformationNCI:highlychemo-sensitiveP388leukemiacellline抗癌药研究专题知识讲座第5页Target-basedscreeningforanti-cancerdrugdiscoveryIdentificationandvalidationoftargetEmergingtargetsDrugdesignandHTS抗癌药研究专题知识讲座第6页IdentificationandvalidationoftargetGenomicsanalytictechnology:microarrayanalysis,high-throughtRNAi,Ambion,Inc.

CenixBioScienceProteomicsanalytictechnology:affinitychromatographyandmassspectrometry

X-omicsanalytictechnologyEpigenomics(DNAmethylationandhistonedeacelylation),Cytomics,Metabolomics,Interatomics,Bioinformomics

抗癌药研究专题知识讲座第7页EmergingtargetsOncogenesandapoptosis-inhibitinggenes,mainlyencodingproteinsthatarecomponentsofsignaltransductionpathwaysthatregulateproliferation,differentiation,invasion/metastasis,angiogenesisand/ortumorapoptosisorcelldeathTargetsfacilitatingtumor-microenvironmentinteractionsandmetastasistheMoffittCancerCenter

DrugDiscoveryProgramattheUniversityofSouthFloridaUniversityofIllinois:FoxM1InhibitorsareAnticancerDrugsthatInduceCellDeath抗癌药研究专题知识讲座第8页targetingWntsignalingmiRNAs,HedgehogsignalingtheNotchpathwaymetabolicpathwaystheimmunesystemspecificinflammatorymediatorsTGFβsignalingpathwaymacrophagestimulatingprotein(MSP)anditsreceptorRonRhoGTPasesignalingnetworktheIGFsignalingnetworkApoptosisandcellcycle:Ras,aGTPase,Raf/Mek,Erk1/2,PI3K/Akt,p53,CDK4,CDK4activatorcyclinD1,CDK4inhibitorp16,Bcl-2genes抗癌药研究专题知识讲座第9页Structure-BasedDrugDesign&VirtualScreeningX-raycrystalstructuresand/orhomologymodelsVirtualscreening(VS)technologies:

computationally“dock”smallmoleculesintotheactivesitesofourmoleculartargetsVisualizeandprobemolecularinteractionsin3Dusingadvancedcomputationalgraphicssystemstounderstandtheforcesthatcontributetoenhancedbinding抗癌药研究专题知识讲座第10页High-SpeedAnaloging:

parallelsynthesisandhigh-throughputpurificationtechniquescoupledwithcomputationalchemistryinput,enablestherapidgenerationof

intelligentlydesignediterationsofnovelcompoundlibrariestoexpediteour“HTShit-to-lead”and“leadoptimization”drugdiscoveryprocessesstronghardwareplatform,state-of-the-artsoftwaresuites抗癌药研究专题知识讲座第11页High-throughputScreening(HTS)

Incubatingthetargetproteinwithmixturesofupto500compoundsatatime.SizeExclusionchromatography(SEC):seperatinghitsfromunboundcompoundsmassspectrometry(LC-MS):identifyingthebinders

Anindustrial-scaleroboticcherry-pickerretrievesordersofscreening“hits”forconfirmationtesting

within24hours抗癌药研究专题知识讲座第12页MetabolicandPhysicochemicalProfiling

Solubilityandpermeability,howwelladrugisabsorbedMetabolizationbysubcellularlivermicrosomesPredictpossibledrug-druginteractions,testingtheirinhibitoryeffectoncytochromeP450enzymesIdentifythosecompoundsthathavethegreatestchanceofsucceedingasdrugsMolecularImaging,

luminescenceandfluorescenceimaging,

visualizeandquantitatenon-invasivelyspecificmoleculartargets,biochemicalpathwaysandphysiologicaleffectsofnoveldrugcandidatesinvivo抗癌药研究专题知识讲座第13页SuccessmolecularlytargeteddrugsAll-trans-retinoicacidforacutepromyelocyticleukemiaimatinib(STI-571)forchronicmyelogenousleukemia

抗癌药研究专题知识讲座第14页target-basedscreeningforanti-cancerdrugdiscoveryShortcomings:

CannotdiscoverasmallmoleculethatrestoresproteinfunctionPharmacologiceffectofthecompoundatacellularororganismlevelmaybeinfluencedSolution:AgaindoingCell-basedassays1.drug’spharmacologiceffectsatthecellularlevel2.discoverynewtargets

Target-basedandcell-basedscreeningfornewanticancerdrugsinthemoleculartargetingeraarecomplementarymethods抗癌药研究专题知识讲座第15页CancerresistanceCancerstemcellsareindeedmoreresistanttotherapythanothercancercellsandmightbethereasonwhyconventionalchemotherapy,whilereducingtumorsize,doesnotresultinlong-termcuresAnalyzedthecancerstemcellsintenpatient-derivedtumorsimplantedinlaboratorymiceand