Successful Drug Discovery, Volume 5

305 Pages·2021·8.735 MB·English

by  Janos Fischer (editor), Christian Klein (editor), Wayne E. Childers (editor)

SuccessfulDrugDiscovery
Successful Drug Discovery
Volume5
Edited by
János Fischer
Christian Klein
Wayne E. Childers
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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