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Protein kinases as drug targets / edited by Bert Klebl, Gerhard Müller, and Michael Hamacher. — Weinheim : Wiley-VCH, c2011. – (63.319/P967) |
Contents
Contents
List of Contributors XI
Preface XV
A Personal Foreword XVII
Part One Hit Finding and Profiling for Protein Kinases: Assay Development and Screening， Libraries 1
1 In Vitro Characterization of Small-Molecule Kinase Inhibitors 3
1.1 Introduction 3
1.2 Optimization of a Biochemical Kinase Assay 4
1.3 Measuring the Binding Affinity and Residence Time of Unusual Kinase Inhibitors
Washout Experiments 18
1.4 Addressing ADME Issues of Protein Kinase Inhibitors in Early Drug Discovery 26
2 Screening for Kinase Inhibitors: From Biochemical to Cellular Assays
2.1 Introduction 45
2.2 Factors that Influence Cellular Efficacy of Kinase Inhibitors 47
2.3 Assays for Measurement of Cellular Kinase Activity 55
2.4 Outlook 63
References 64
3 Dissecting Phosphorylation Networks: The Use of Analogue-Sensitive Kinases and More Specific Kinase Inhibitors as Tools 69
3.1 Introduction 69
3.2 Chemical Genetics 71
3.3 The Application of AS KA Technology in Molecular Biology 76
3.4 Conclusions and Outlook 80
References 81
Part Two Medicinal Chemistry 85
4 Rational Drug Design of Kinase Inhibitors for Signal Transduction Therapy 87
4.1 The Concept of Rational Drug Design 88
4.2 3D Structure-Based Drug Design 89
4.3 Ligand-Based Drug Design 92
4.4 Target Selection and Validation 93
4.5 Personalized Therapy with Kinase Inhibitors 96
4.6 The NCLTM Technology and Extended Pharmacophore Modeling(Prediction-Oriented QSAR) 99
4.7 Non-ATP Binding Site-Directed or Allosteric Kinase Inhibitors 101
4.8 The Master Keys for Multiple Target Kinase Inhibitors 102
4.9 Conclusions 107
References 109
5 Kinase Inhibitors in Signal Transduction Therapy 115
5.1 VEGFR (Vascular Endothelial Growth Factor Receptor) 115
5.2 Flt3 (FMS-Like Tyrosine Kinase 3) 116
5.3 Bcr-Abl (Breakpoint Cluster Region-Abelson Murine Leukemia Viral Oncogene Homologue) 118
5.4 EGFR (Epidermal Growth Factor Receptor) 118
5.5 IGFR (Insulin-Like Growth Factor Receptor) 120
5.6 FGFR (Fibroblast Growth Factor Receptor) 120
5.7 PDGFR (Platelet-Derived Growth Factor Receptor) 121
5.8 c-Kit 121
5.9 Met (Mesenchymal-Epithelial Transition Factor) 122
5.10 Src 123
5.11 p38 MAPKs (Mitogen-Activated Protein Kinases) 123
5.12 ERK1/2 124
5.13 JNK (c-Jun N-Terminal Kinase， MAPK8) 126
5.14 PKC (Protein Kinase C) 126
5.15 CDKs (Cyclin-Dependent Kinases) 127
5.16 Auroras 127
5.17 Akt/PKB (Protein Kinase B) 129
5.18 Phosphoinositide 3-Kinases 129
5.19 Syk (Spleen Tyrosine Kinase) 130
5.20 JAK (Janus Kinase) 130
5.21 Kinase Inhibitors in Inflammation and Infectious Diseases 131
References 134
6 Design Principles of" Deep Pocket-Targeting Protein Kinase Inhibitors ]45
6.1 Introduction 145
6.2 Classification of Protein Kinase Inhibitors 147
6.3 Type II Inhibitors 150
6.4 Common Features of Type II Inhibitors 154
6.5 Design Strategies for Type II Inhibitors 155
6.6 Comparative Analysis of the Different Design Strategies 180
6.7 Conclusions and Outlook 187
References 190
7 From Discovery to Clinic: Aurora Kinase Inhibitors as Novel Treatments for Cancer 195
7.1 Introduction 195
7.2 Biological Roles of the Aurora Kinases 195
7.3 Aurora Kinases and Cancer 196
7.4 In Vitro Phenotype of Aurora Kinase Inhibitors 197
7.5 Aurora Kinase Inhibitors 203
7.6 X-Ray Crystal Structures of Aurora Kinases 221
7.7 Summary 221
References 222
Part Three Application of Kinase Inhibitors to Therapeutic Indication Areas 229
8 Discovery and Design of Protein Kinase Inhibitors: Targeting the Cell cycle in Oncology 231
8.1 Protein Kinase Inhibitors in Anticancer Drug Development 231
8.2 Structure-Guided Design of Small-Molecule Inhibitors of the Cyclin-Dependent Kinases 233
8.3 Catalytic Site Inhibitors 234
8.4 ATP Site Specificity 236
8.5 Alternate Strategies for Inhibiting CDKs 239
8.6 Cyclin Groove Inhibitors (CGI) 240
8.7 Inhibition of CDK-Cyclin Association 242
8.8 Recent Developments in the Discovery and the Development of Aurora Kinase Inhibitors 242
8.9 Development of Aurora Kinase Inhibitors through Screening and Structure-Guided Design 244
8.10 Aurora Kinase Inhibitors in Clinical Trials 248
8.11 Progress in the Identification of Potent and Selective Polo-Like Kinase Inhibitors 250
8.12 Development of Small-Molecule Inhibitors of PLK1 Kinase Activity 252
8.13 Discovery of Benzthiazole PLK1 Inhibitors 254
8.14 Recent Structural Studies of the Plk1 Kinase Domain 255
8.15 Additional Small-Molecule PLK1 Inhibitors Reported 256
8.16 The Polo-Box Domain 257
8.17 Future Developments 259
References 259
9 Medicinal Chemistry Approaches for the Inhibition of the p38 MAPK Pathway 271
9.1 Introduction 271
9.2 p38 MAP Kinase Basics 271
9.3 p38 Activity and Inhibition 275
9.4 First-Generation Inhibitors 278
9.5 Pyridinyl-Imidazole Inhibitor: SB203580 278
9.6 N-Substituted Imidazole Inhibitors 282
9.7 N，N’-Diarylurea-Based Inhibitors: BIRB796 286
9.8 Structurally Diverse Clinical Candidates 288
9.9 Medicinal Chemistry Approach on VX-745-Like Compounds 297
9.10 Conclusion and Perspective for the Future 301
References 302
10 Cellular Protein Kinases as Antiviral Targets 305
10.1 Introduction 305
10.2 Antiviral Activities of the Pharmacological Cyclin-Dependent Kinase Inhibitors
10.3 Antiviral Activities of Inhibitors of Other Cellular Protein Kinases 338
10.4 Conclusion 339
References 341
11 Prospects for TB Therapeutics Targeting Mycobacterium tuberculosis Phosphosignaling Networks 349
11.1 Introduction 349
11.2 Rationale for Ser/Thr Protein Kinases and Protein Phosphatases as Drug Targets
11.3 Drug Target Validation by Genetic Inactivation 351
11.4 STPK Mechanisms， Substrates， and Functions 352
11.5 M. tuberculosis STPK Inhibitors 355
11.6 Conclusions and Prospects 359
References 359
Index 365
