Suto,Ph.D.DiscoveryDivisionResearch - PDF document

Suto,Ph.D.DiscoveryDivisionResearchSuto
Suto,Ph.D.DiscoveryDivisionResearchSuto@southernresearch.orgTargetsValidationDruggabiltyTargetsValidationDruggabiltyBackgroundWhatinvolvedestablishingdiscoveryprojectBiologicalrelevancechemicaltractabilityFocusValidatedtargetWhatvalidatedtargetyoumakethatdeterminationExamplesDruggabletargetWhatDruglikeness–Viabilit

yfordiscoveryBiologicalrelevancechemica
yfordiscoveryBiologicalrelevancechemicaltractabilityBiologicalrelevancechemicaltractabilityDruDiscoverDevelomentypTarget IdentificationTargetPrioritization/ValidationTarget Prioritization/ValidationLead IdentificationLead OptimizationPreclinical TestingChemical Manufacturing Controls (CMC)/PharmaceuticsPhar

macology/ToxicologyPharmacology/Toxicol
macology/ToxicologyPharmacology/ToxicologyInvestigational New Drug (IND)/CTX/CTAPhase IPhase IIPhase IIINew Drug Approval (NDA)/MAAPhIIIb/IVPhase Post MarketDrugdevelopmenttakesyearsyearsyearsyearsyearsyearsDiscoverypreclinicaltestingyearsI2yearsyearsyearsFDAreview(postmarketingtesting)developWhyexp

ensive?MoreregulationsrequirementsMore
ensive?MoreregulationsrequirementsMoreregulationsrequirementsLargefailureRatecompoundsentering1makemanydiscoveryprogramsaremanydrugdiscoveryprogramsareTypicalLargeAveragesTypicalLargeAveragesStartscreeningprograms/assaysStartscreeningprograms/assaystargetspramstableppursueLimitedBackupcompoundsAdvanc

eintolatestageoptimizationprograms/comp
eintolatestageoptimizationprograms/compoundsproceedintoWhy?WhyFailAChangingParadigm”Pharmacokineticspropertiesdistribution,metabolism,excretionRodentvs.vs.monkeyvs.ToxicologypredictedstudiesAdverseeffectsAdverseeffectsefficacyBiologicalrationaleincorrectRelevanceRelevanceratsrheumatoidpatientsOncologyCommercialrea

sonsCommercialreasonsPreclinicalDisco
sonsCommercialreasonsPreclinicalDiscoveryPreclinicalDiscoveryTargetidentificationvalidationthrougscreeninglidentiicationvitrochemicaltractabilitytargetstargetscardiovascular,chemistryoptimizationvitroStability,solubility,cyotochromeenzymes,proteinbinding,transportersToxicologyvivoassessmentvivoassessment

vivooptimizationvivopharmacokinetics,bio
vivooptimizationvivopharmacokinetics,bioavailability,safetyNominationcandidateTargetIdentificationTargetIdentificationKeystepsfortargettargetvalidateddruggableyouscreenformodulators?Agonist,antagonist,inhibitorOutcomeforWheretarget!!dffSeconaryassaysdierencestesthypothesisStandardscompoundsPditbilitPtayofel

BiomarkersClinicaloutcomeFailureRate'
BiomarkersClinicaloutcomeFailureRate'sFailureRateAlzheimersclinicalfailureratethatclinicalfailureratethattherapeuticareasmodifyingapprovedamodifyingdrugapprovedthatrecreateshistopathologicalneurodegenerationhistopathologicalneurodegenerationhallmarksMayhavetargetareasMayhavetargetareasbrainTargets

validatedbetterTargetsvalidatedbetter
validatedbetterTargetsvalidatedbetterWhatDiscoveryTargetWhataDiscoveryTargetProteinsReceptorsenzymessurfaceproteincoupledreceptorsproteincoupledreceptorsProteaseTranscriptionfactorsltiregutitransportersInfectiouscancerDirectassaysProteinproteininteractionsSenicapocSenicapocPotassiuminhibitorfortreatment

(KCa3.1)inhibitorRBC’smaintainhydrationv
(KCa3.1)inhibitorRBC’smaintainhydrationvivoefficacyAdvancedclinicalpatientslPositivehVasoocclusiveratewasapprovablepointThreestudySenicapochydroxyureacombinationSenicapochydroxyureacombinationIndependentreviewboardanalyzeddataconcludedwouldbenefitwasstoppedwasstoppedTherewasimprovementseveralhematologicalfactorsin

dicatingbiologicalvalidated/druggabletar
dicatingbiologicalvalidated/druggabletarget?TherapeuticWhereDiscovery(targets)From?Historicallyfromnaturalproductswivestale?snakevenomObservedvivoeffectsObservedvivoeffectsChemistcompoundsfoundtestClinicalobservationfftdidfftedeRationaleapproachesbiochemistry/biologyScreening,systemsUnderstandinggeneticmutations

NewTargetIdentificationNewTargetIden
NewTargetIdentificationNewTargetIdentificationNewerroacheshaveidentifiedmoretarproteomics,pharmacogenomicsinterferencerelatedtechnologiesinterfering(geneInterferenceexpressiongenePathwayanalysisPathwayanalysisTransgenicKeyQuestionTargetValidationModulatetargetwhateffecthave?WhatConstitutesValidatedtargetWhatCo

nstitutesaValidatedtargetGeneticmuta
nstitutesaValidatedtargetGeneticmutationsproteinassociatedpgamyloidprecursorproteinsecretaseidlgrowfrecep2breastcancerpromotescancergrowthpulationaprocessgpInflammationCyclooxygenaseProteomefamilKCNQ2–ValidatedTargetsPresent at high levels in neurons including dorsal root ganglia (DRG). No signific

ant expression in major peripheral organ
ant expression in major peripheral organs. iiCQ2dCQ3idihKCNQ/3ValidatedTargets•Mutatin KCN and K associate wh a congenital seizure disorder in humans –Benign Familial Neonatal ConvulsionsTargeted deletion of KCNQ2 in mice increases sensitivity to chemoconvulsant induced seizures.neuronal M-current –control r

esting membrane potential, integrationo
esting membrane potential, integrationofsynapticinputsandspikefrequencyadaptation.integration KCNQ/M-current activators are efficacious in animal models and human diseases associated with excessive neuronal ibiliexcty.KCNQFamilyKCNQFamilyKCNQcontributes to cardiac action potential repolarization. M

utation can result in Long QT Syndrome-
utation can result in Long QT Syndrome-Forms heterotetramers with KCNQ3. Mutations in KCNQ2causethecongenitalseizuredisorderbenignfamilialKCNQ2 neonatal convulsions (BFNC).-Expresses poorly as a homomultimer. Co-assembles withotherKCNQchannelssuchasKCNQ2andKCNQ5with Mutations in KCNQ3 also

linked to BFNC-Expressed primarily in i
linked to BFNC-Expressed primarily in inner ear. Mutation linked to one form of hereditary deafness.-Expressed in nervous system and co-assembles with TypicalAssayProgressionEpilepsy–ICASH-SY-5Y DRCLQT1+minK, L-type Ca, hERGDRCSH-SY-5Y DRCLQT1+minK, L-type Ca, hERGDRCKCNQ2/Q3, KCNQ3/Q5 DRC (flux)InRat MES screen I

n vitro ADMECYP, PPB, LM, Sol Earlyasse
n vitro ADMECYP, PPB, LM, Sol Earlyassessment10mg/kg w/ plasma/brain levels and estimate of metabolitesKCNQ2/3, hERGEPInElectrophysiologyPK profile rat IV/POMES and LMA EDTherapeuticindexDefinitiveFurther ion channel selectivity 2iPK(%FT1/2)Carrageenan, chung, formalinEfficacySafety(CNS liability channels and o

ther cardiac channels)Receptor Binding2
ther cardiac channels)Receptor Binding2ndspeces T1/2)7-day ToxCyclooxygenaseInhibitorsValidatedTargetclassicalCOXinhibitorsareselectiveCOXresultingprostaglandinthromboxanesynthesiseffectreducedinflammation,wellantipyretic,antithromboticanalgesiceffects.•mostfrequentadverseeffectNSAIDsirritation•mostfrequentadve

rseeffectNSAIDsirritationgastricmuco
rseeffectNSAIDsirritationgastricmucosaprostaglandinshaveprotectiverolegastrointestinaltract.NSAIDsaremaycausedamagegastrointestinaltract.CyclooxygenaseInhibitorsCOXCOX2researchersdiscoveredthattwodifferentCOXenzymesexisted,knownCOXCOX•COXknownpresentmost•COX1knownpresentmosttract,COXmaintainsstomach.enzymeinv

olvedkidneyplateletCOXiilifltiCOX2i
olvedkidneyplateletCOXiilifltiCOX2ispresenatsofinonCOXCOXconvertarachidonicCOX1COX2convertarachidonicprostaglandin,resultinginflammation,makeCOXundesirableCOXconsidereddesirableCOX2considereddesirableCOXInhibitorsCOX2InhibitorsCelecoxibRofecoxibCOXinflamedtheregastricirritationassociatedC

OXinhibitors,decreasedulceration.COXinh
OXinhibitors,decreasedulceration.COXinhibitorshavefoundincreaseatherothrombosis–analysisrandomizedalmostAanalysisrandomizedalmostparticipantsshowedthatselectiveCOXinhibitorsareassociatedmoderatelyincreasedvascularevents,twofoldincreasedmyocardialinfarctionValidated,druggabledata??data??InhibitorsThiAliierapeutA

ppLocalanestheticLidocaineProcaineEpi
ppLocalanestheticLidocaineProcaineEpilepsyEpilepsyPhenytoinAntiarrythmicsMexiliteneTAMBOCOR™(flecainideMexitilNeuropathicareselectiveareselectiveAffectValidatedtargets?Protein name Gene Expression profile Associated human channelopathiesfbilGEFS(lkCentral neurons, [peripheral neurons] and cardiac myocytes

febrepepsGEFSravet syndromel
febrepepsGEFSravet syndromelnown as severe myclonic epilepsof infancy or SMEI), borderline SMEI (SMEB), West syndrome (also known as infantile spasms), Doose syndrome (also known as myoclonic astatic epilepsy), intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC), Panayiotopoulos sy

ndrome, familial hemiplegic migraine (FH
ndrome, familial hemiplegic migraine (FHM), familial autism, Rasmussens's encephalitis and Lennox-Gastaut syndrome[7]Central neurons, peripheral neurons inherited febrile seizures and epilepsyCentral neurons, peripheral neurons and cardiac myocytes none known NaSkeletal musclehyperkalemic periodic paralysisparamyoto

nia congenitapotassium-aggravated myot
nia congenitapotassium-aggravated myotoniaCardiac myocytes, uninnervated skeletal muscle, central neurons Long QT syndromeBrugada syndrome, and idiopathic ventricular fibrillation CtldltC neurons, dorsa root gangliaperipheral neuronsheart, glia cells none known Dorsal root gangliasympathetic neurons, Schwan

n cells, and erythromelalgiaPEPDchan
n cells, and erythromelalgiaPEPDchannelopathy-associated insensitivity to pain and recently discovered a disabling form of fibromyalgia (rs6754031 polymorphism - PMID: 22348792),neuroendocrine cells 22348792).Dorsal root ganglia none known Dorsal root ganglia none known heart, uterus, skeletal muscle, astroctes

dorsal root none knownxy,ganglion c
dorsal root none knownxy,ganglion cells CongenitalPain:NovelInFrameDeletionMutationsFrameDeletionMutationsencodesvoltagegatedavproteinexpressedneurons.MutationscausethreepdisordersallelicmutationsresultChannelopathyassociatedPain–whereasactivatinmutationscausesevereppgppParoxysmalExtremePainDisorderPr

imaryErythermalgiattithtibilit•Tod
imaryErythermalgiattithtibilit•TodatatiinthatcausecompteiexperienceareproteintruncatingpresumablyproteinproducedTargetValidated?WhenaTargetValidated?Mhacstudi–oecastcstudesOverexpression,antimutationsstudies–knockoutstudiesTherapeuticinterventionbiologicalclinicalresultsNDAapprovalDiscuss

ionDiscussion•Validatedtarget“drugg
ionDiscussion•Validatedtarget“druggabletarget”Validatedtarget.druggabletargetdiff?•theredifferencedruggabletargetTypesTypesNaturalproductsNaturalproductsSteroids,antibioticsPeptidesPeptides(smaller)BiologicalsAntibodies,proteins,antisenseOralbioavailability,manufacture,stability,costNew“Validated

”TargetCidCtar“druWhatevidencethere
”TargetCidCtar“druWhatevidencethereinitiatingdiscoveryprogram?inhibitorsinhibitors,,differences,biomarkerRelatedknowntargetsFamiliesphatases,receptorsStructuralinformationProteincrystallographicdatastructureProteincrystallographicdata,structureIntellectualpropertyFamiliesGeneFamiliesAgfamilagroug

thatshareortantgypcharacteristics.ma
thatshareortantgypcharacteristics.manycases,genesfamilyshareblockscasesgenesaregroupedtogether–cases,genesaregroupedtogetherafamilybecauseproteinsproducedfromgenesworktogetherparticipateprocessfamilydiscoveryProgramsexpertisedirectedtowardcertaintargetsdirectedtowardcertaintargetsForexample,assays,chemistr

y,discoveryTypesFamiliesDruggableTarg
y,discoveryTypesFamiliesDruggableTargetsGproteincoupledreceptorsGproteincoupledreceptors•Kinases•ProteasesProteasesreceptorsPhosphatasesPhosphatasesPhosphodiesterasesFamilycationTwoporePotassiumSoluteEAG/ERG/ELKKCNQInteresting epilepsy and pain targets based on: EAG/ERG/ELKFunction, Distribution and Ph

armacologyThe IUPHAR name for the KCNQ
armacologyThe IUPHAR name for the KCNQ family is Kv7.xGProteinReceptorsGProteinReceptorsWorldMarketforProteinRecetorsppTargetingReachAccordingReportIndustryAnalystsIndustryAnalysts,releasecomprehensivereportProteinCopledReceptorsmarketmarketforProteinProteinuReceptorsmarket.marketforGProteinRecept

orsprojectedreachyearfactorsgrowthmarket
orsprojectedreachyearfactorsgrowthmarketinterestresearchersfortargets,increasedhowmembranestructuresadvancementsidentificationwellstructures,advancementsidentificationwellcrystallizationnewerstructures.emergenceefficientpowerfultechnologiesscreeningexpectedstimulatemarketgrowth.GPCRGPCRantaonists–ZantacUlcersBeta

blockers–BystolicHypertensionBetaagonis
blockers–BystolicHypertensionBetaagonists–SymbicortAsthmaAsthmaSerotoninAgonists–SumatriptanraineFocusedlibraries–GPCR’sDevelopexpertiseDevelopexpertiseChemicalstructurehERGblockersPerry M et al. J Physiol 2010;588:3157-3167FamilyProblemDrggableTargetsProblemtuggableTargets2                Â

 Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â
 Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Lg       3                                                                                                   gAdaptedfromAldrich                     Â

 Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â
 Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Representativethattargetdifferentcalciumnifedipine,verapamil,diltiazemforcardiovascularindicationsziconitideforcancer(i.t.administration)zonisamidemibefradil(epilepsyTzonisamide,,mibefradil(epilepsyTypeAntagonistsTargetValidationatureesugge

stsTtlciumeaueedecesuggesscacu
stsTtlciumeaueedecesuggesscacuareinvolvedcertaindisordersantisense,rodentknockoutstudiesIdentifynovelcalciumtitagontsevainlsofTargetvalidation–ICvs.(brain?)concentrationse50foldselectivee,SelectiveversusrelevanttargetsOrallybioavailable,(i.v.rat)5foldoverCmax)•5foldoverCmax)BlockersDbl

SllMllAtitruggaMolAntagontsP
SllMllAtitruggaMolAntagontsPain(taxol)109:150161)(Dogrul105:159Epilepsy61).2197).3695.ArousalstatesArousalstatesdeltawavesdisturbancesrapideyemovementTypecalciumOncologyroleTypecalciumhepatocellularcarcinomaproliferationOncologyReportsSummarySummaryIdentifiednovel,potent,antagonistsPanantagonistsversusfami

lySelectiveversusrelatedfamilcardiacy
lySelectiveversusrelatedfamilcardiacyvitropropertiescanachievedPermeabilitystabilityPermeability,stabilityOralbioavailabilitycanachievedCaco2assayssynthesisLimitedexposureconcentrationsinsufficientforindicationsIndications–TTypeInhibitorsIndicationsTTypeInhibitorsParkinson’sParkinsonsNeruroprotectiondid

ersDruggable,yes,validated,maybeDrug
ersDruggable,yes,validated,maybeDruglikelikeMoleculesRuleof55–5,donors5H,g,,acceptorsatoms)Remarks:moreviolation;applicableforsubstratestransportersnaturalproducts•ExtensPolarsurfaceareadonors,acceptorsrotatableacceptors,rotatableDruglikenessDruglikeness•OptimalwaterfatyOrallyadministered

throughintestinallining,carriedpenetrate
throughintestinallining,carriedpenetratemembranereachmembranereachacLogP,estimatesolubility.potency–Reducestargetpharmacologygivenconcentration–clearance,potencyallowsforlowtotalclearance,potencyallowsforlowtotallowersidiosyncraticreactionsyougivebetterLikeOptimizationGuidingOptimizationSeveralscorinmeth

odscanressgpdruglikenesspotencyphysic
odscanressgpdruglikenesspotencyphysicochemicalproperties,forexampleligandefficiencyefficiencyefficiencyefficiencyPotencyAvoidsubstructuresthathavechemicalpharmacologicalproperties.nitronitrocompoundsacceptors,arealkylatingagentspotentiallymutageniccarcinogenicpotentiallymutageniccarcinogenicNaturalProductsNa

turalProductsVeryeffectiveVeryeffect
turalProductsVeryeffectiveVeryeffectiveOptimizednature’tlikeconceptDontlikeconceptVerycomplexManystereocentersManystereocentersMoredifficultworkcomebackacomebackStreptomycinStreptomycinFormulamassg/molPredictingDruggabilityPredictingDruggabilityIdentifiedproteinDruggableComputationalapproachesdevel

opedDruggabilitysoftwareDruggabilitys
opedDruggabilitysoftwareDruggabilitysoftwareChemicalInformationdbiliRulthgoverndruggaAlgorithmisolatecharacterizepocketsVolume,enclosure,surfacearea,chargedresidues,Volume,enclosure,surfacearea,chargedresidues,aromatic,hydrophobicresiduesRemainstestedSuto,Ph.D.DiscoveryDivisionResearchSuto@southernresea