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 FLT3 .................................................. 165
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 JAK2 .................................................. 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 P13K/PTEN Pathway ................................. 266
5.1.1 P13K ........................................... 267
5.1.2 PDK1 ........................................... 270
5.1.3 АКТ ............................................ 271
5.1.4 Other AGC Kinases .............................. 273
5.1.5 P13K 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 МАРК 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 С ...................................... 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
References ................................................. 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 .......................................... 349
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 ................................................. 368
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 ....................................... 448
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 TGFP 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 С 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
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