Targeting Protein Kinases for Cancer Therapy

TARGETING PROTEIN KINASES FOR CANCER THERAPY......Page 5
CONTENTS......Page 7
Preface......Page 13
Acknowledgments......Page 15
1.1 A Brief History of Protein Phosphorylation......Page 17
1.2 Kinases and Cancer......Page 19
1.3 A Tour of the Human Protein Kinase Superfamily......Page 24
1.3.1 Tyrosine Kinase Group......Page 28
1.3.2 TKL (Tyrosine Kinase-like) Group......Page 38
1.3.3 STE Group......Page 41
1.3.4 CSNK1 Group......Page 43
1.3.5 AGC Group......Page 44
1.3.6 CAMK Group......Page 46
1.3.7 CMGC Group......Page 48
1.3.9 Others......Page 52
1.3.11 Nonprotein Kinases......Page 57
1.4 Strategic Considerations for Selecting Kinases as Drug Targets......Page 62
1.5.2 Alternative Strategies for Kinase Inhibition......Page 67
References......Page 74
2 PROTEIN KINASE STRUCTURE, FUNCTION, AND REGULATION......Page 91
2.1.1 EGF:EGF Receptor Interactions......Page 92
2.1.2 Insulin:Insulin Receptor and IGF1:IGF1R......Page 94
2.1.3 FGF:FGF Receptor (Heparin/Heparan Sulfate) Interactions......Page 95
2.1.5 Angiopoietin2:TIE2 Receptor Interactions......Page 96
2.1.7 The Role of Transmembrane Domains......Page 98
2.2 Protein Kinase Domain Structure and Function......Page 99
2.3.1 Steady State Kinetics......Page 103
2.3.2 Chemistry of Protein Kinase Catalysis......Page 105
2.4 Protein Kinase Regulation......Page 107
2.4.1 Regulation Via Activation Segment Phosphorylation......Page 108
2.4.2 Regulation by N-Terminal Sequences and Domains......Page 112
2.4.3 C-Terminal Regulatory Regions......Page 114
2.4.4 Regulation by Other Domains and Partner Proteins......Page 118
References......Page 123
3 RECEPTOR TYROSINE KINASES......Page 135
3.1 EGF/ERBB Receptors......Page 136
3.1.1 ERBB Receptors and Cancer......Page 144
3.2 Insulin/IGF Receptors......Page 146
3.2.1 Insulin/IGF Receptors and Cancer......Page 150
3.3 Anaplastic Lymphoma Kinase......Page 152
3.3.1 ALK and Cancer......Page 153
3.4 VEGF Receptors (VEGFR1, VEGFR2, VEGFR3)......Page 156
3.5 PDGF Receptors......Page 162
3.5.1 PDGFRs and Cancer......Page 165
3.6 FGF Receptors......Page 169
3.6.1 FGFRs and Cancer......Page 172
3.7 KIT......Page 174
3.7.1 KIT and Cancer......Page 176
3.8 FLT3......Page 181
3.8.1 FLT3 and Cancer......Page 183
3.9 RET......Page 184
3.9.1 RET and Thyroid Carcinoma......Page 185
3.10.1 MET......Page 186
3.10.2 RON......Page 191
References......Page 193
4 NONRECEPTOR TYROSINE KINASES......Page 231
4.1 ABL......Page 232
4.2 ARG......Page 239
4.3 SRC and SRC Family Kinases......Page 240
4.3.1 SRC......Page 244
4.3.2 Cellular Roles of SRC......Page 248
4.3.3 SRC and Cancer......Page 250
4.4 FAK......Page 251
4.5 JAK2......Page 254
4.5.1 Activation and Known Mutations and Fusions of the JAK Family of Tyrosine Kinases......Page 257
4.5.2 Further Roles of JAK2 in Tumor Growth......Page 259
References......Page 262
5 INTRACELLULAR SIGNAL TRANSDUCTION CASCADES......Page 281
5.1 The PI3K/PTEN Pathway......Page 282
5.1.1 PI3K......Page 283
5.1.2 PDK1......Page 286
5.1.3 AKT......Page 287
5.1.4 Other AGC Kinases......Page 289
5.1.5 PI3K Pathway Activation in Cancer......Page 291
5.2.1 mTOR......Page 295
5.2.2 p70S6 Kinase......Page 298
5.2.3 mTOR Pathway Activation in Cancer......Page 299
5.3 MAPK Signaling Pathways......Page 300
5.3.1 ERK/MAPK Signaling......Page 301
5.3.2 RAF Family Kinases......Page 302
5.3.3 MEK and ERK Kinases......Page 305
5.3.4 ERK/MAPK Pathway Activation in Cancer......Page 307
5.4 PIM Kinases......Page 309
5.5 Protein Kinase C......Page 310
5.5.1 PKC Activation......Page 311
5.5.2 Classical PKCs......Page 314
5.5.3 Novel PKCs......Page 315
5.5.4 Atypical PKCs......Page 316
References......Page 317
6.1 Cyclin-Dependent Kinases (CDKs) and Cell Cycle Progression......Page 343
6.1.1 Introduction......Page 344
6.1.2 CDK4 and CDK6......Page 348
6.1.3 CDK2......Page 350
6.1.5 CDK1......Page 353
6.1.7 CCRK/CDCH/p42......Page 357
6.2.1 Introduction......Page 358
6.2.2 CDK7......Page 360
6.2.3 CDK8......Page 362
6.2.4 CDK9......Page 363
6.2.5 CDK11......Page 365
6.2.6 CDK12 (CDC2-Related Kinase CRKRS)......Page 366
6.2.7 CDK13 (CDC2L5)......Page 367
6.3.1 CDK5......Page 368
6.3.2 GAK......Page 369
6.4 Mitotic Kinases......Page 370
6.4.1 PLKs......Page 372
6.4.2 Aurora Kinases......Page 375
6.5 Cell Cycle Checkpoint Kinases......Page 377
6.5.1 ATM, ATR, and DNAPK......Page 378
6.5.2 CHK1, CHK2, and MAPKAPK2......Page 380
References......Page 384
7 STRUCTURAL BIOCHEMISTRY OF KINASE INHIBITORS......Page 407
7.1.1 Targeting the Active Versus Inactive Form......Page 408
7.1.2 ATP-Competitive Versus Noncompetitive Inhibitors......Page 409
7.1.3 Specific Versus Multitargeted Inhibitors......Page 410
7.2 Architecture of the ATP Binding Site: DFG-in......Page 412
7.3 Case Study: Inhibitors of CHK1......Page 415
7.4 Case Study: Inhibitors of CDK2......Page 423
7.5 Case Study: Inhibitors of SRC Family Kinases......Page 429
7.6 Case Study: EGF Receptor Inhibitors......Page 432
7.7 Targeting the Inactive Conformation......Page 436
7.7.1 Binding Mode of Imatinib......Page 437
7.7.2 Binding of BAY-43-9006 (Sorafenib) to the Inactive BRAF Kinase......Page 439
7.8 Noncompetitive Inhibition......Page 440
7.9 Kinase Inhibitor Specificity......Page 442
References......Page 445
8.1 BCR-ABL Inhibitors......Page 451
8.2 SRC Inhibitors......Page 462
8.3 JAK2 Inhibitors......Page 464
8.4 EGFR/ERBB Inhibitors......Page 468
8.4.1 Determinants of Response and Resistance to ERBB Inhibitors......Page 471
8.5 IGF1R Inhibitors......Page 486
8.6 FLT3 Inhibitors......Page 488
8.7 KIT Inhibitors......Page 496
8.8 MET/RON Inhibitors......Page 506
8.9 RET Inhibitors......Page 512
8.10.1 FAK......Page 514
8.10.2 TGFβ Receptor......Page 515
References......Page 516
9.1 Introduction......Page 543
9.2 Angiokinase Inhibitors......Page 546
References......Page 571
10.1 mTOR Inhibitors......Page 583
10.1.1 Clinical Pharmacodynamics and Tolerability of mTOR Inhibitors......Page 585
10.2 PI3K Inhibitors......Page 594
10.3 RAF Kinase Inhibitors......Page 598
10.4 MEK Inhibitors......Page 600
10.5 CDK Inhibitors......Page 603
10.6 Cell Cycle Checkpoint Kinase Inhibitors......Page 609
10.7.1 PLK Inhibitors......Page 613
10.7.2 Aurora Kinase Inhibitors......Page 615
10.8 Protein Kinase C Inhibitors......Page 620
References......Page 621
11.1 Kinase Inhibitor Drug Resistance......Page 639
11.1.1 Efflux Pumps and Drug Transporters......Page 642
11.1.2 Other DMPK Factors......Page 643
11.1.3 Target Mutation......Page 644
11.1.4 Target Overexpression and Activation......Page 647
11.1.5 Downstream Pathway Activation......Page 648
11.1.6 Redundant Receptors/Pathways......Page 649
11.2 Combination Therapy With Kinase Inhibitors......Page 651
11.2.1 Angiogenesis Inhibitors and Chemotherapy......Page 653
11.2.2 Survival Pathway Inhibitors and Chemotherapy/Targeted Therapy......Page 654
11.2.3 DNA Damage Checkpoint Inhibitors and Chemotherapy......Page 655
11.2.4 RTK Switching: Targeting Receptor Redundancy......Page 656
11.3 Systems Biology and Translational Medicine......Page 657
11.3.1 Classification of Tumors and Prediction of Response: Expression Profiling......Page 658
11.3.2 Phosphoprotein Analysis, Kinomics, and Systems-Based Approaches......Page 661
11.3.3 Translational Medicine......Page 663
11.4 Conclusions......Page 668
References......Page 669
List of Abbreviations......Page 681
Index......Page 705