Targeting Protein Kinases for Cancer Therapy Book

Preface xi

Acknowledgments xiii

1 Kinases and Cancer 1

1.1 A Brief History of Protein Phosphorylation 1

1.2 Kinases and Cancer 3

1.3 A Tour of the Human Protein Kinase Superfamily 8

1.3.1 Tyrosine Kinase Group 12

1.3.2 TKL (Tyrosine Kinase-like) Group 22

1.3.3 STE Group 25

1.3.4 CSNK1 Group 27

1.3.5 AGC Group 28

1.3.6 CAMK Group 30

1.3.7 CMGC Group 32

1.3.8 RGC Group 36

1.3.9 Others 36

1.3.10 Atypical Protein Kinases 41

1.3.11 Nonprotein Kinases 41

1.4 Strategic Considerations for Selecting Kinases as Drug Targets 46

1.5 Comparison of Kinase Inhibitor Therapeutic Strategies 51

1.5.1 Small Molecule Versus Antibody-Directed Therapies 51

1.5.2 Alternative Strategies for Kinase Inhibition 51

References 58

2 Protein Kinase Structure, Function and Regulation 75

2.1 Ligand Binding to Receptor Tyrosine Kinases 76

2.1.1 EGF: EGF Receptor Interactions 76

2.1.2 Insulin: Insulin Receptor and IGF1:IGF1R 78

2.1.3 FGF: FGF Receptor (Heparin/Heparan Sulfate) Interactions 79

2.1.4 VEGF: VEGF Receptor Interactions 80

2.1.5 Angiopoietin2: TIE2 Receptor Interactions 80

2.1.6 Ephrin: EPH Receptor Interactions 82

2.1.7 The Role of Transmembrane Domains 82

2.2 Protein Kinase Domain Structure and Function 83

2.3 Catalytic Activity of Protein Kinases 87

2.3.1 Steady State Kinetics 87

2.3.2 Chemistry of Protein Kinase Catalysis 89

2.4 Protein Kinase Regulation 91

2.4.1 Regulation Via Activation Segment Phosphorylation 92

2.4.2 Regulation by N-Terminal Sequences and Domains 96

2.4.3 C-Terminal Regulatory Regions 98

2.4.4 Regulation by Other Domains and Partner Proteins 102

References 107

3 Receptor Tyrosine Kinases 119

3.1 EGF/ERBB Receptors 120

3.1.1 ERBB Receptors and Cancer 128

3.2 Insulin/IGF Receptors 130

3.2.1 Insulin/IGF Receptors and Cancer 134

3.3 Anaplastic Lymphoma Kinase 136

3.3.1 ALK and Cancer 137

3.4 VEGF Receptors (VEGFR1, VEGFR2, VEGFR3) 140

3.5 PDGF Receptors 146

3.5.1 PDGFRs and Cancer 149

3.6 FGF Receptors 153

3.6.1 FGFRs and Cancer 156

3.7 KIT 158

3.7.1 KIT and Cancer 160

3.8 FLT 3165

3.8.1 FLT3 and Cancer 167

3.9 RET 168

3.9.1 RET and Thyroid Carcinoma 169

3.10 MET and RON 170

3.10.1 MET 170

3.10.2 RON 175

References 177

4 Nonreceptor Tyrosine Kinases 215

4.1 ABL 216

4.2 ARG 223

4.3 SRC and SRC Family Kinases 224

4.3.1 SRC 228

4.3.2 Cellular Roles of SRC 232

4.3.3 SRC and Cancer 234

4.4 FAK 235

4.4.1 FAK and Cancer 238

4.5 JAK 238

4.5.1 Activation and Known Mutations and Fusions of the JAK Family of Tyrosine Kinases 241

4.5.2 Further Roles of JAK2 in Tumor Growth 243

References 246

5 Intracellular Signal Transduction Cascades 265

5.1 The PI3K/PTEN Pathway 266

5.1.1 PI3K 267

5.1.2 PDK1 270

5.1.3 AKT 271

5.1.4 Other AGC Kinases 273

5.1.5 PI3K Pathway Activation in Cancer 275

5.2 mTOR Signaling 279

5.2.1 mTOR 279

5.2.2 p70S6 Kinase 282

5.2.3 mTOR Pathway Activation in Cancer 283

5.3 MAPK Signaling Pathways 284

5.3.1 ERK/MAPK Signaling 285

5.3.2 RAF Family Kinases 286

5.3.3 MEK and ERK Kinases 289

5.3.4 ERK/MAPK Pathway Activation in Cancer 291

5.4 PIM Kinases 293

5.5 Protein Kinase C 294

5.5.1 PKC Activation 295

5.5.2 Classical PKCs 298

5.5.3 Novel PKCs 299

5.5.4 Atypical PKCs 300

Reference 301

6 Cell Cycle Control 327

6.1 Cyclin-Dependent Kinases (CDKs) and Cell Cycle Progression 327

6.1.1 Introduction 328

6.1.2 CDK4 and 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 CDKs and mRNA Production 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 348

6.2.6 CDK12 (CDC2-Related Kinase CRKRS) 350

6.2.7 CDK13 (CDC2L5) 351

6.3 Other CDK-Related Kinases 352

6.3.1 CDK5 352

6.3.2 GAK 353

6.4 Mitotic Kinases 354

6.4.1 PLKs 356

6.4.2 Aurora Kinases 359

6.5 Cell Cycle Checkpoint Kinases 361

6.5.1 ATM, ATR, and DNAPK 362

6.5.2 CHK1, CHK2, and MAPKAPK2 364

References 364

7 Structural Biochemistry of Kinase Inhibitors 391

7.1 Strategies for Inhibitor Design 392

7.1.1 Targeting the Active Versus Inactive Form 392

7.1.2 ATP-Competitive Versus Noncompetitive Inhibitors 393

7.1.3 Specific Versus Multitargeted Inhibitors 394

7.2 Architecture of the ATP Binding Site: DFG-in 396

7.3 Case Study: Inhibitors of CHK1 399

7.4 Case Study: Inhibitors of CDK2 407

7.5 Case Study: Inhibitors of SRC Family Kinases 413

7.6 Case Study: EGF Receptor Inhibitors 416

7.7 Targeting the Inactive Conformation 420

7.7.1 Binding Mode of Imatinib 421

7.7.2 Binding of BAY-43-9006 (Sorafenib) to the Inactive BRAF Kinase 423

7.8 Noncompetitive Inhibition 424

7.9 Kinase Inhibitor Specificity 426

References 429

8 Tyrosine Kinase Inhibitors 435

8.1 BCR-ABL Inhibitors 435

8.2 SRC Inhibitors 446

8.3 JAK2 Inhibitors 443

8.4 EGFR/ERBB Inhibitors 452

8.4.1 Determinants of Response and Resistance to ERBB Inhibitors 455

8.5 IGF1R Inhibitors 470

8.6 FLT3 Inhibitors 472

8.7 KIT Inhibitors 480

8.8 MET/RON Inhibitors 490

8.9 RET Inhibitors 496

8.10 Other Inhibitors 498

8 10.1 FAK 498

8.10.2 TGFβ Receptor 499

References 500

9 Angiokinase Inhibitors 527

9.1 Introduction 527

9.2 Angiokinase Inhibitors 530

References 555

10 Intracellular Signaling Kinase Inhibitors 567

10.1 mTOR Inhibitors 567

10.1.1 Clinical Pharmacodynamics and Tolerability of mTOR Inhibitors 569

10.2 PI3K Inhibitors 578

10.3 RAF Kinase Inhibitors 582

10.4 MEK Inhibitors 584

10.5 CDK Inhibitors 587

10.6 Cell Cycle Checkpoint Kinase Inhibitors 593

10.7 Mitotic Kinase Inhibitors 597

10.7.1 PLK Inhibitors 597

10.7.2 Aurora Kinase Inhibitors 599

10.8 Protein Kinase C Inhibitors 604

References 605

11 Current Challenges and Future Directions 623

11.1 Kinase Inhibitor Drug Resistance 623

11.1.1 Efflux Pumps and Drug Transporters 626

11.1.2 Other DMPK Factors 627

11.1.3 Target Mutation 628

11.1.4 Target Overexpression and Activation 631

11.1.5 Downstream Pathway Activation 632

11.1.6 Redundant Receptors/Pathways 633

11.2 Combination Therapy With Kinase Inhibitors 635

11.2.1 Angiogenesis Inhibitors and Chemotherapy 637

11.2.2 Survival Pathway Inhibitors and Chemotherapy/Targeted Therapy 638

11.2.3 DNA Damage Checkpoint Inhibitors and Chemotherapy 639

11.2.4 RTK Switching: Targeting Receptor Redundancy 640

11.3 Systems Biology and Translational Medicine 641

11.3.1 Classification of Tumors and Prediction of Response: Expression Profiling 642

11.3.2 Phosphoprotein Analysis, Kinomics, and Systems-Based Approaches 645

11.3.3 Translational Medicine 647

11.4 Conclusions 652

References 653

List of Abbreviations 665

Index 689