Targeting Protein Kinases for Cancer Therapy / Edition 1 available in Hardcover, eBook
Targeting Protein Kinases for Cancer Therapy / Edition 1
- ISBN-10:
- 0470229659
- ISBN-13:
- 9780470229651
- Pub. Date:
- 02/15/2010
- Publisher:
- Wiley
Targeting Protein Kinases for Cancer Therapy / Edition 1
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$179.95Overview
Research has shown that protein kinases can instigate the formation and spread of cancer when they transmit faulty signals inside cells. Because of this fact, pharmaceutical scientists have targeted kinases for intensive study, and have been working to develop medicinal roadblocks to sever their malignant means of communication.
Complete with full-color presentations, Targeting Protein Kinases for Cancer Therapy defines the structural features of protein kinases and examines their cellular functions. Combining kinase biology with chemistry and pharmacology applications, this book enlists emerging data to drive the discovery of new cancer-fighting drugs. Valuable information includes:
- Comprehensive overviews of the major kinase families involved in oncology, integrating protein structure and function, and providing important tools to assist pharmaceutical researchers to understand and work in this dynamic area of cancer drug research
- Focus on small molecule inhibitors as well as other therapeutic modalities
- Discussion of kinase inhibitors that have entered clinical trials for the treatment of cancer, with an emphasis on molecules that have progressed to late stage clinical trials and, in a few cases, to market
Providing a platform for further study, this important work reviews both the successes and challenges of kinase inhibitor therapy, and provides insight into future directions in the war against cancer.
Product Details
| ISBN-13: | 9780470229651 |
|---|---|
| Publisher: | Wiley |
| Publication date: | 02/15/2010 |
| Pages: | 720 |
| Product dimensions: | 6.00(w) x 9.40(h) x 1.50(d) |
About the Author
MARY E. GERRITSEN is Vice President of Molecular and Cellular Pharmacology at Exelixis, where she is in charge of cell-based screening in preclinical research and of biomarker studies for clinical development compounds in Phase I and II studies. Her prior industry experience includes positions at Genentech, Bayer and Millennium Pharmaceuticals. She has authored more than one hundred peer-reviewed articles and twenty-six book chapters and is an inventor on forty-two issued patents.
Table of Contents
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
What People are Saying About This
"This excellent book is a comprehensive review of protein kinases in the context of their roles in human cancer. ... [It] is an excellent resource for scientists involved in selecting potential drug targets and optimization of compounds that are likely to be effective. The involvement of protein kinases in cancer, and strategies for selecting drug targets is thoughtfully discussed, and protein structures, domains and sites of regulation are described in depth and in ways that are easy to follow and understand. Individual kinases are described from the biological perspective and in the context of efforts to target them, often with case studies to illustrate specific points in exquisite detail. Understanding these proteins at this level of detail is essential to understand how they can be targeted and what we can expect to observe in the clinic. Following description of the kinases themselves and their function and regulation in signaling pathways, and cell cycle control, the second half of this book describes kinase inhibitors and experience gained from analyzing these compounds in vitro and in vivo. The final chapter addresses challenges and future directions, including issues relating to combinational therapy and systems biology. These big issues complete the comprehensive tour of the world of kinases in the context of cancer, from molecular details of drug-protein interactions, through biology to clinical application. Considering the success so far in targeting these enzymes in the clinic, and the level of investment currently being made to developing new kinase inhibitors for cancer therapy, there is no doubt that this outstanding book will be a valuable asset to the large community of chemists, biologists and clinicians involved in developing the next generation of therapies." —Frank McCormick, Director, UCSF Helen Diller Family Comprehensive Cancer Center