Targeting Protein Kinases for Cancer Therapy

781 Pages·18.708 MB·English

by  David J. Matthews, Mary E. Gerritsen(auth.)

TARGETING PROTEIN
KINASES FOR CANCER
THERAPY
TARGETING PROTEIN
KINASES FOR CANCER
THERAPY
David J. Matthews
Mary E. Gerritsen
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LibraryofCongressCataloging-in-PublicationData:
Matthews,DavidJ.(DavidJohn),1965–
Targetingproteinkinasesforcancertherapy/DavidJ.Matthews,MaryE.Gerritsen.
p.;cm.
Includesbibliographicalreferencesandindex.
ISBN978-0-470-22965-1(cloth)
1.Proteinkinases–Inhibitors–Therapeuticuse.2.Antineoplasticagents.3.Protein
kinases.I.Gerritsen,MaryE.II.Title.
[DNLM:1.Neoplasms–drugtherapy.2.ProteinKinaseInhibitors–therapeuticuse.3.
DrugDiscovery.4.DrugResistance,Neoplasm.5.ProteinKinases–physiology.6.Protein-
TyrosineKinases–antagonists&inhibitors.QZ267M438t2009]
RC271.P76M382009
615(cid:2).798–dc22
2009020804
PrintedintheUnitedStatesofAmerica
10987654321
CONTENTS
Preface xi
Acknowledgments xiii
1 KINASESANDCANCER 1
1.1 A BriefHistoryofProteinPhosphorylation 1
1.2 KinasesandCancer 3
1.3 A Tourof theHuman ProteinKinaseSuperfamily 8
1.3.1 TyrosineKinaseGroup 12
1.3.2 TKL(TyrosineKinase-like)Group 22
1.3.3 STE Group 25
1.3.4 CSNK1Group 27
1.3.5 AGCGroup 28
1.3.6 CAMKGroup 30
1.3.7 CMGCGroup 32
1.3.8 RGCGroup 36
1.3.9 Others 36
1.3.10 AtypicalProteinKinases 41
1.3.11 NonproteinKinases 41
1.4 StrategicConsiderationsforSelectingKinasesas DrugTargets 46
1.5 Comparisonof KinaseInhibitorTherapeuticStrategies 51
1.5.1 Small MoleculeVersusAntibody-DirectedTherapies 51
1.5.2 AlternativeStrategiesforKinaseInhibition 51
References 58
2 PROTEINKINASESTRUCTURE,FUNCTION,ANDREGULATION 75
2.1 LigandBindingto ReceptorTyrosineKinases 76
2.1.1 EGF:EGFReceptorInteractions 76
2.1.2 Insulin:InsulinReceptorand IGF1:IGF1R 78
2.1.3 FGF:FGFReceptor(Heparin/HeparanSulfate)Interactions 79
2.1.4 VEGF:VEGFReceptorInteractions 80
2.1.5 Angiopoietin2:TIE2ReceptorInteractions 80
2.1.6 Ephrin:EPHReceptor Interactions 82
2.1.7 TheRoleof TransmembraneDomains 82
2.2 ProteinKinaseDomainStructureand Function 83
2.3 CatalyticActivityofProteinKinases 87
2.3.1 Steady StateKinetics 87
2.3.2 ChemistryofProteinKinaseCatalysis 89
2.4 ProteinKinaseRegulation 91
2.4.1 RegulationViaActivationSegment Phosphorylation 92
v
vi CONTENTS
2.4.2 RegulationbyN-TerminalSequencesand Domains 96
2.4.3 C-TerminalRegulatoryRegions 98
2.4.4 RegulationbyOtherDomainsand PartnerProteins 102
References 107
3 RECEPTORTYROSINEKINASES 119
3.1 EGF/ERBBReceptors 120
3.1.1 ERBBReceptorsandCancer 128
3.2 Insulin/IGFReceptors 130
3.2.1 Insulin/IGFReceptorsandCancer 134
3.3 AnaplasticLymphomaKinase 136
3.3.1 ALK andCancer 137
3.4 VEGFReceptors(VEGFR1,VEGFR2,VEGFR3) 140
3.5 PDGFReceptors 146
3.5.1 PDGFRsandCancer 149
3.6 FGFReceptors 153
3.6.1 FGFRsandCancer 156
3.7 KIT 158
3.7.1 KITandCancer 160
3.8 FLT3 165
3.8.1 FLT3 and Cancer 167
3.9 RET 168
3.9.1 RETand ThyroidCarcinoma 169
3.10 METand RON 170
3.10.1 MET 170
3.10.2 RON 175
References 177
4 NONRECEPTORTYROSINEKINASES 215
4.1 ABL 216
4.2 ARG 223
4.3 SRCand SRCFamilyKinases 224
4.3.1 SRC 228
4.3.2 CellularRolesof SRC 232
4.3.3 SRCand Cancer 234
4.4 FAK 235
4.4.1 FAK andCancer 238
4.5 JAK2 238
4.5.1 ActivationandKnownMutationsand Fusionsof theJAK Familyof
TyrosineKinases 241
4.5.2 FurtherRolesofJAK2 inTumorGrowth 243
References 246
5 INTRACELLULARSIGNALTRANSDUCTIONCASCADES 265
5.1 ThePI3K/PTENPathway 266
5.1.1 PI3K 267
CONTENTS vii
5.1.2 PDK1 270
5.1.3 AKT 271
5.1.4 OtherAGCKinases 273
5.1.5 PI3KPathway ActivationinCancer 275
5.2 mTOR Signaling 279
5.2.1 mTOR 279
5.2.2 p70S6Kinase 282
5.2.3 mTOR Pathway ActivationinCancer 283
5.3 MAPKSignalingPathways 284
5.3.1 ERK/MAPKSignaling 285
5.3.2 RAFFamily Kinases 286
5.3.3 MEK andERK Kinases 289
5.3.4 ERK/MAPKPathwayActivationinCancer 291
5.4 PIMKinases 293
5.5 ProteinKinaseC 294
5.5.1 PKCActivation 295
5.5.2 ClassicalPKCs 298
5.5.3 NovelPKCs 299
5.5.4 AtypicalPKCs 300
References 301
6 CELLCYCLECONTROL 327
6.1 Cyclin-DependentKinases(CDKs)and CellCycleProgression 327
6.1.1 Introduction 328
6.1.2 CDK4and CDK6 332
6.1.3 CDK2 334
6.1.4 CDK3 337
6.1.5 CDK1 337
6.1.6 CDK10 341
6.1.7 CCRK/CDCH/p42 341
6.2 CDKsand mRNAProduction 342
6.2.1 Introduction 342
6.2.2 CDK7 344
6.2.3 CDK8 346
6.2.4 CDK9 347
6.2.5 CDK11 349
6.2.6 CDK12(CDC2-RelatedKinaseCRKRS) 350
6.2.7 CDK13(CDC2L5) 351
6.3 OtherCDK-RelatedKinases 352
6.3.1 CDK5 352
6.3.2 GAK 353
6.4 MitoticKinases 354
6.4.1 PLKs 356
6.4.2 AuroraKinases 359
6.5 CellCycleCheckpointKinases 361
6.5.1 ATM, ATR,and DNAPK 362
6.5.2 CHK1,CHK2,andMAPKAPK2 364
References 368
viii CONTENTS
7 STRUCTURALBIOCHEMISTRYOFKINASEINHIBITORS 391
7.1 StrategiesforInhibitorDesign 392
7.1.1 TargetingtheActiveVersusInactiveForm 392
7.1.2 ATP-CompetitiveVersusNoncompetitiveInhibitors 393
7.1.3 SpecificVersusMultitargetedInhibitors 394
7.2 Architectureof theATP BindingSite:DFG-in 396
7.3 CaseStudy:InhibitorsofCHK1 399
7.4 CaseStudy:InhibitorsofCDK2 407
7.5 CaseStudy:InhibitorsofSRC FamilyKinases 413
7.6 CaseStudy:EGFReceptor Inhibitors 416
7.7 TargetingtheInactiveConformation 420
7.7.1 BindingModeofImatinib 421
7.7.2 Bindingof BAY-43-9006(Sorafenib)totheInactiveBRAFKinase 423
7.8 NoncompetitiveInhibition 424
7.9 KinaseInhibitorSpecificity 426
References 429
8 TYROSINEKINASEINHIBITORS 435
8.1 BCR-ABLInhibitors 435
8.2 SRCInhibitors 446
8.3 JAK2Inhibitors 448
8.4 EGFR/ERBBInhibitors 452
8.4.1 DeterminantsofResponseandResistancetoERBB Inhibitors 455
8.5 IGF1RInhibitors 470
8.6 FLT3 Inhibitors 472
8.7 KITInhibitors 480
8.8 MET/RONInhibitors 490
8.9 RETInhibitors 496
8.10 OtherInhibitors 498
8.10.1 FAK 498
8.10.2 TGFβReceptor 499
References 500
9 ANGIOKINASEINHIBITORS 527
9.1 Introduction 527
9.2 AngiokinaseInhibitors 530
References 555
10 INTRACELLULARSIGNALINGKINASEINHIBITORS 567
10.1 mTOR Inhibitors 567
10.1.1 ClinicalPharmacodynamicsand TolerabilityofmTOR Inhibitors 569
10.2 PI3KInhibitors 578
10.3 RAFKinaseInhibitors 582
10.4 MEK Inhibitors 584
10.5 CDKInhibitors 587
10.6 CellCycleCheckpointKinaseInhibitors 593
10.7 MitoticKinaseInhibitors 597
CONTENTS ix
10.7.1 PLK Inhibitors 597
10.7.2 AuroraKinaseInhibitors 599
10.8 ProteinKinaseC Inhibitors 604
References 605
11 CURRENTCHALLENGESANDFUTUREDIRECTIONS 623
11.1 KinaseInhibitorDrugResistance 623
11.1.1 Efflux Pumpsand DrugTransporters 626
11.1.2 OtherDMPK Factors 627
11.1.3 Target Mutation 628
11.1.4 Target Overexpressionand Activation 631
11.1.5 DownstreamPathway Activation 632
11.1.6 RedundantReceptors/Pathways 633
11.2 CombinationTherapy WithKinaseInhibitors 635
11.2.1 AngiogenesisInhibitorsand Chemotherapy 637
11.2.2 SurvivalPathway InhibitorsandChemotherapy/TargetedTherapy 638
11.2.3 DNA DamageCheckpointInhibitorsand Chemotherapy 639
11.2.4 RTK Switching:TargetingReceptorRedundancy 640
11.3 SystemsBiologyand TranslationalMedicine 641
11.3.1 ClassificationofTumorsand PredictionofResponse:
ExpressionProfiling 642
11.3.2 PhosphoproteinAnalysis,Kinomics,andSystems-Based Approaches 645
11.3.3 TranslationalMedicine 647
11.4 Conclusions 652
References 653
ListofAbbreviations 665
Index 689
x CONTENTS
These Appendices referred to in the text can be found on Wiley ftp site at
the following address:
ftp://ftp.wiley.com/public/sci_tech_med/protein_kinase
AppendixI TumorAssociatedMutationsinEGFR
AppendixII TumorAssociatedMutationsinERBB2
AppendixIII TumorAssociatedMutationsinALK
AppendixIV TumorAssociatedMutationsinPDGFRα
AppendixV TumorAssociatedMutationsinFGFR1
AppendixVI TumorAssociatedMutationsinFGFR2
AppendixVII TumorAssociatedMutationsinFGFR3
AppendixVIII TumorAssociatedMutationsinFGFR4
AppendixIX TumorAssociatedMutationsinKIT
AppendixX TumorAssociatedMutationsinFLT3
AppendixXI TumorAssociatedMutationsinRET
AppendixXII TumorAssociatedMutationsinMET
AppendixXIII TumorAssociatedMutationsinJAK2
AppendixXIV TumorAssociatedMutationsinPIK3CA
AppendixXV TumorAssociatedMutationsinBRAF
AppendixXVI TumorAssociatedKinaseDomainMutationsinABL
PREFACE
Protein kinases are among the most critical and widely studied cellular signaling
moleculesandregulateessentiallyallprocessescentraltothegrowth,development,
andhomeostasisofeukaryoticcells.Inthe1980s,proteinkinaseswerefirstshown
to have an important role in oncogenesis and tumor progression, and since then
they have received increasing attention as targets for anticancer drugs. Several
kinaseinhibitorsarenowapprovedforthetreatmentofcancer,andmanymoreare
advancingthroughclinicaltrials.InTargetingProteinKinasesforCancerTherapy,
we provide an integrated view of kinase cancer targets and the drugs that inhibit
them,withafocus onsmallmoleculeinhibitors. Wehavesoughttocoverthe field
broadly,andalthoughsometargets,pathways,anddrugsarecoveredindepth,some
have of necessity only been covered briefly. We have included many references
to both review articles and primary literature, but apologize to colleagues whose
work could not be cited due to limitations of space.
Throughout this book, proteins are denoted by their most widely accepted
abbreviationincapitalletters(seeListofAbbreviations)andoftenadditionalnames
bywhichtheproteinisknownarealsoprovided.Thehumangenes(usingtheabbre-
viations of the Human Genome Nomenclature Committee (www.genenames.org))
are denoted by italic capital letters. Genes from lower organisms are denoted by
italiclowercaseletters.Viralproteinsorgenesaredenotedbytheprefixv-.Protein
kinase structures (discussed mainly in Chapters 2 and 7) are referenced by their
protein data bank (PDB) accession code and can be accessed at www.rcsb.org.
In Chapter 1, we review the human kinome—the superfamily of over 500
protein kinases, many of which have been implicated in tumorigenesis and the
proliferation and survival of cancer cells. We also consider various approaches for
the discovery and validation of kinase cancer targets, and some of the therapeu-
tic modalities that have been employed apart from small molecule inhibitors of
kinase domains. Here we meet a recurring theme: many kinases appear to be dual
agents with regard to cancer, in that depending on the cellular context in which
they operate, they can either promote or inhibit tumor formation and progression.
Chapter 2 introduces the structural features of protein kinases. We discuss vari-
ous modes of receptor:ligand interaction used by receptor tyrosine kinases, then
turn our attention to the catalytic properties and various regulatory mechanisms of
the kinase catalytic domain itself. Chapter 3 presents a review of some prominent
receptortyrosine kinases,whichto date have receivedthe mostattentionas cancer
targets. In Chapter 4, we move inside the cell membrane and focus on the non-
receptor tyrosine kinases. Chapters 5 and 6 introduce various intracellular kinase
signalingpathwaysthataredysregulatedintumorcells andthathave receivedsig-
nificantattentionforthedevelopmentofanticancerdrugs.Theseincludeacomplex,
xi