Successful Drug Discovery, Volume 5 PDF
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SuccessfulDrugDiscovery Successful Drug Discovery Volume5 Edited by János Fischer Christian Klein Wayne E. Childers Editors AllbookspublishedbyWiley-VCHarecarefully produced.Nevertheless,authors,editors,and JánosFischer publisherdonotwarranttheinformationcontained RichterCo.,Plc. inthesebooks,includingthisbook,tobefreeof PharmaResearch errors.Readersareadvisedtokeepinmindthat Gyömröiut19/21 statements,data,illustrations,proceduraldetailsor 1103Budapest otheritemsmayinadvertentlybeinaccurate. Hungary LibraryofCongressCardNo.: ChristianKlein appliedfor RocheInnovationCenterZurich CancerImmunotherapyDiscovery BritishLibraryCataloguing-in-PublicationData Wagistrasse10 Acataloguerecordforthisbookisavailablefromthe 8952Schlieren BritishLibrary. Switzerland BibliographicinformationpublishedbytheDeutsche WayneE.Childers Nationalbibliothek TempleUniversitySchoolofPharmacy TheDeutscheNationalbibliothekliststhis MoulderCtr.forDrugDiscoveryRes. publicationintheDeutscheNationalbibliografie; 3307NBroadStreet detailedbibliographicdataareavailableonthe PA Internetat<http://dnb.d-nb.de>. UnitedStates ©2021WILEY-VCHGmbH,Boschstr.12,69469 Cover Weinheim,Germany Supportedbythe InternationalUnionofPureandApplied Allrightsreserved(includingthoseoftranslation Chemistry(IUPAC) intootherlanguages).Nopartofthisbookmaybe ChemistryandHumanHealthDivision reproducedinanyform–byphotoprinting, POBox13757 microfilm,oranyothermeans–nortransmittedor ResearchTrianglePark,NC2770-3757 translatedintoamachinelanguagewithoutwritten USA permissionfromthepublishers.Registerednames, trademarks,etc.usedinthisbook,evenwhennot specificallymarkedassuch,arenottobeconsidered unprotectedbylaw. PrintISBN:978-3-527-34754-4 ePDFISBN:978-3-527-82685-8 ePubISBN:978-3-527-82686-5 oBookISBN:978-3-527-82687-2 Typesetting SPiGlobal,Chennai,India Printedonacid-freepaper 10 9 8 7 6 5 4 3 2 1 v Contents AdvisoryBoardMembers xi Preface xiii PartI GeneralAspects 1 1 DrugDiscoveryinAcademia 3 OliverPlettenburg 1.1 Introduction 3 1.2 RepurposingDrugs 5 1.2.1 ThalidomideDerivatives 5 1.2.2 Chemotherapy:NitrogenMustards 6 1.3 Pregabalin 8 1.4 NaturalProduct-DerivedDrugDiscovery 10 1.4.1 Antibiotics 11 1.4.2 AnticancerDrugs 12 1.4.2.1 Camptothecin 12 1.4.2.2 Taxol 14 1.4.2.3 Epothilones 17 1.4.2.4 Eribulin 18 1.4.3 ArtemisininandArtemether 20 1.4.4 Carfilzomib 21 1.5 BiologicDrugs 23 1.5.1 Insulin 23 1.5.2 Rituximab 25 1.5.3 Alglucerase 26 1.6 ConceptionallyNewSmallMoleculeDrugs 27 1.6.1 HistoneDeacetylaseInhibitors 27 1.6.2 AcyclicNucleosidePhosphonates 29 1.6.3 Darunavir 31 1.6.4 Sunitinib 32 1.7 SweetSpotforAcademicDrugDiscovery 34 ListofAbbreviations 36 vi Contents References 37 Biography 46 2 FromDegraderstoMolecularGlues:NewWaysofBreaking DownDisease-AssociatedProteins 47 YvonneA.Nagel,AdrianBritschgiandAntonioRicci 2.1 Introduction 47 2.2 DefinitionandHistoricalDevelopmentofDegraders 47 2.3 TheUbiquitin–ProteasomeSystemandConsiderationsofE3Ligases 53 2.4 GeneralDesignAspects 55 2.5 DifferentiationoftheDegraderTechnologytoTraditional Approaches 58 2.5.1 TheAbilitytoExpandtheDruggableProteome 58 2.5.2 OvercomingtheAccumulationofTargetProtein 59 2.5.3 AbrogatingScaffoldingFunctions 59 2.5.4 CreatingTargetSpecificity 60 2.5.5 CatalyticModeofAction 60 2.5.6 Event-DrivenPharmacologyandProlongedPDEffect 61 2.6 PotentialDisadvantagesandLimitationsofDegraders 62 2.7 MolecularGlue-likeDegradersandMonovalentDegraders 64 2.7.1 DefinitionsandHistoricalPerspective 64 2.7.2 StateoftheArt 67 2.8 FutureDirections(StatusQ32020) 70 2.9 SummaryandConclusions 71 Acknowledgments 71 ListofAbbreviations 72 References 73 Biographies 84 PartII DrugClassStudies 87 3 GLP-1ReceptorAgonistsfortheTreatmentofType2Diabetes andObesity 89 LarsLinderoth,JacobKofoed,JánosT.Kodra,SteffenReedtz-Rungeand ThomasKruse 3.1 Introduction 89 3.2 GLP-1Biology 90 3.2.1 GLP-1ReceptorBindingandActivation 91 3.2.2 GLP-1PharmaceuticalDevelopments 92 3.3 Ex4-BasedAnalogues 92 3.3.1 Exenatide 92 3.3.2 ExenatideLAR 94 3.3.3 Lixisenatide 94 3.3.4 Efpeglenatide 94 Contents vii 3.3.5 PegylatedLoxenatide 95 3.4 GLP-1BasedAnalogues 95 3.4.1 Liraglutide 95 3.4.2 Semaglutide 96 3.4.3 Taspoglutide 97 3.4.4 AlbiglutideandAlbenatide 98 3.4.5 Dulaglutide 98 3.5 Co-agonists 99 3.5.1 GLP-1/GIPCo-agonists 100 3.5.2 GLP-1/GlucagonCo-agonists 100 3.5.2.1 OtherGLP-1RAgonists 100 3.6 Summary 102 ListofAbbreviations 103 References 104 Biographies 108 4 RecentAdvancesonSGLT2Inhibitors:SyntheticApproaches, TherapeuticBenefits,andAdverseEvents 111 AnaM.deMatos,PatríciaCalado,WilliamWashburnandAméliaP.Rauter 4.1 Introduction 111 4.2 TheMechanismofActionofSGLT2Inhibitors 112 4.3 SyntheticApproachestoGliflozins 113 4.3.1 Dapagliflozin 114 4.3.2 Sotagliflozin 119 4.3.3 Empagliflozin 119 4.3.4 Bexagliflozin 122 4.3.5 Luseogliflozin 123 4.3.6 Tofogliflozin 125 4.3.7 Ertugliflozin 128 4.3.8 Ipragliflozin 129 4.3.9 Canagliflozin 130 4.3.10 Remogliflozin 133 4.4 ClinicalBenefitsofSGLT2Inhibitors 134 4.4.1 ReductioninHbA Levels 134 1C 4.4.2 ProtectionAgainstCardiovascularEventsinDiabeticPatients 137 4.4.3 RenoprotectioninPatientswithT2D 139 4.4.4 BodyweightReduction 140 4.5 SafetyProfileandParticularlyRelevantAdverseEventsAssociatedwith SGLT2Inhibitors 141 4.6 ApplicationofSGLT2InhibitorsinType1Diabetes 143 4.7 Conclusions 145 Acknowledgments 146 ListofAbbreviations 146 References 148 Biographies 155 viii Contents 5 CARTCells:ANovelBiologicalDrugClass 159 WhitneyGladney,JulieJadlowsky,MeganM.DavisandAndrewFesnak 5.1 Introduction 159 5.2 ABriefHistoryofCell-BasedTherapies 159 5.3 GeneticallyEngineeredTCellTherapyProducts 162 5.3.1 TCellReceptor-EngineeredTCells 162 5.3.1.1 IntrotoTCRs 162 5.3.1.2 ChallengeswithTCR-EngineeredTCells 165 5.3.2 CARTCells 165 5.3.2.1 WhatIsaCAR? 165 5.3.2.2 WhyDoYouPutaCARintoaTCell(asOpposedtoAnotherCell)? 167 5.4 CARTCells:TheLivingDrug 169 5.4.1 EarlySignalsofCARTCellEfficacy 169 5.4.2 CART19Pharmacokinetics 170 5.4.2.1 Expansion 170 5.4.2.2 Persistence 171 5.4.2.3 Trafficking 172 5.4.3 BiomarkersofCARTCellQuality 172 5.4.4 SideEffectsofCARTCellTherapy 173 5.4.4.1 CytokineReleaseSyndrome 173 5.4.4.2 CARTCellAssociatedNeurotoxicity 174 5.4.4.3 On-Target,Off-TumorToxicities 175 5.4.5 ChallengesEncounteredwithTherapeuticApplicationofCART Cells 176 5.4.5.1 ProductionIssues 176 5.4.5.2 TherapeuticResistance 179 5.5 TranslationfromLaboratoryInnovationtoApprovedTherapy 183 5.6 FutureDirectionsandCARTProgramstoConsider 186 5.6.1 ApprovedTherapies 186 5.6.2 Pre-registrationTherapies 187 5.7 AdditionalResourcesforSupplementaryInformationonCellular Therapies,IncludingRegulations,Notifications,andGuidelines 188 ListofAbbreviations 190 References 192 Biographies 197 6 CGRPInhibitorsfortheTreatmentofMigraine 199 SarahWalterandMarceloE.Bigal 6.1 Introduction 199 6.2 TheOverallPhysiologicalRoleofCGRP 200 6.3 TheRoleofCGRPintheGut 203 6.4 WhatIstheRoleofCGRPinMigraine? 203 6.4.1 Small-MoleculeAntagonists 204 6.4.2 Large-MoleculeAntagonists 208 6.5 RoleofCGRPAntagonistsinOtherIndications 211 6.6 Conclusions 212 Contents ix ListofAbbreviations 212 References 213 Biographies 219 PartIII CaseStudies 221 ⚪ 7 DiscoveryandDevelopmentofEmicizumab(HEMLIBRAR):A HumanizedBispecificAntibodytoCoagulationFactorsIXaand XwithaFactorVIIICofactorActivity 223 TakehisaKitazawa,KoichiroYoneyamaandTomoyukiIgawa 7.1 Introduction 223 7.2 PreclinicalExperiencewithEmicizumab 225 7.2.1 BriefHistoryonDiscoveryofEmicizumab 225 7.2.1.1 IdeaInspirationofanAsymmetricBispecificIgGAntibodytoFIXaand FXwithFVIII-CofactorFunction 225 7.2.1.2 FromtheFirstImmunizationtotheIdentificationoftheClinical Candidate(ACE910=Emicizumab) 226 7.2.2 MechanismofActionandNonclinicalCharacteristicsof Emicizumab 229 7.2.2.1 MechanismofActionandInVitroCharacteristicsofEmicizumab 229 7.2.2.2 InVivoCharacteristicsofEmicizumab 230 7.2.3 MolecularEngineeringTechnologiesIncorporatedinEmicizumabfor IndustrialManufacturing 231 7.2.3.1 ObtainingaCommonLightChain 232 7.2.3.2 SeparationandPurificationfromBy-products 232 7.2.3.3 MinimizingtheAmountofHomodimericBy-products 233 7.2.3.4 ApplicationofTechnology 233 7.2.4 ConclusionsfromPreclinicalStudies 233 7.3 ClinicalExperiencewithEmicizumab 234 7.3.1 Early-PhaseClinicalDevelopment 235 7.3.1.1 PhaseIandI/IIStudies 235 7.3.1.2 ClinicalPharmacologyInvestigations 237 7.3.2 Late-PhaseClinicalDevelopment 239 7.3.2.1 Non-interventionalStudy 239 7.3.2.2 PhaseIIIStudieswithOnce-WeeklyDosinginPatientswithFVIII Inhibitors 239 7.3.2.3 PhaseIIIStudieswithOnce-Weekly,Every-2-Week,orEvery-4-Week DosinginPatientswithorwithoutFVIIIInhibitors 240 7.4 Conclusions 242 Acknowledgments 242 ConflictofInterests 242 ListofAbbreviations 243 References 243 Biographies 247 x Contents 8 DiscoveryandDevelopmentofIvosidenib(AG-120: ⚪ TIBSOVOR) 249 ZenonD.KonteatisandZhihuaSui 8.1 Introduction 249 8.2 CrystalStructureofIDH1 250 8.3 SearchformIDH1Inhibitors 250 8.4 HittoLeadExploration 252 8.5 LeadOptimization:DiscoveryofAG-120 257 8.6 SynthesisofAG-120 260 8.7 PreclinicalCharacterizationofAG-120 261 8.8 IvosidenibClinicalStudies 262 8.9 Conclusions 267 ListofAbbreviations 268 References 268 Biographies 270 ⚪ 9 TheDiscoveryofKisqaliR(Ribociclib):ACDK4/6Inhibitorfor theTreatmentofHR+/HER2−AdvancedBreastCancer 273 ChristopherT.Brain,RajivChopra,SunkyuKim,StevenHowardand MooJeSung 9.1 DiseaseBackground 273 9.2 TargetBackgroundandValidation:TheCellCycle 274 9.3 CommencementofDrugDiscoveryEfforts 276 9.4 Fragment-basedApproach 276 9.5 Cross-ScreeningofExistingKinaseAssetsLeadingtoRibociclib 277 9.6 CombinationTreatmentswithRibociclib 282 9.7 Early-PhaseClinicalStudies 283 9.8 Phase3ClinicalStudies 284 9.9 Conclusions 285 Acknowledgments 285 ListofAbbreviations 285 References 286 Biographies 288 Index 291
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