Contents

Chapter 1 The Kinome and its Impact on Medicinal Chemistry 1

David H. Drewry, Paul Bamborough, Klaus Schneider,

Gary K. Smith

1.1 Introduction 1

1.2 Kinome Scale Assays 81.3 Starting Points for Kinase Probe Discovery: The

benefits of chemical connectivity 16

1.4 Measures of Selectivity 21

1.5 Examples of Selectivity Improvement 23

1.6 Conclusions 26

References 26

Appendix 1.1 30

Chapter 2 Contemporary Approaches to Kinase Lead Generation 54

Iain Simpson and Richard A. Ward

2.1 Introduction 54

2.2 Isoform Selective, PH Domain Dependent Akt

Inhibitors 55

2.3 Exploitation of Inactive Kinase Conformations 57

2.3.1 Switch Pocket Inhibitors 582.3.2 Hydrophobic Motifs 61

2.4 Targeted Kinase Libraries 65

2.5 Structure-based Design 66

2.5.1 Scaffold-Hopping and Hybridisation 66

2.5.2 Fragment-Based Lead Generation 70

2.5.3 Virtual Screening 73

RSC Drug Discovery Series No. 19

Kinase Drug Discovery

Edited by Richard A. Ward and Frederick Goldberg

# Royal Society of Chemistry 2012

Published by the Royal Society of Chemistry, www.rsc.org

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2.6 Summary 75

References 75

Chapter 3 The Learning and Evolution of Medicinal Chemistry against

Kinase Targets 79

Martin E. Swarbrick

3.1 Introduction 79

3.2 Structural Basis of Kinase Inhibition and its Impact on

Selectivity 80

3.3 Translating Isolated Enzyme Inhibition to Efficacy

Against the Native Kinase 88

3.4 Solubility as a Key Developability Propert 90

3.5 Intellectual Property Considerations 91

3.6 Summary 93References 93

Chapter 4 The Mechanisms and Kinetics of Protein Kinase Inhibitors 96

Walter H. J. Ward

4.1 Introduction 96

4.2 Mechanisms of Inhibition 974.2.1 Protein Kinase 3-D Structures 97

4.2.2 Binding Modes for Early Kinase Inhibitors 97

4.2.3 Diverse Binding Modes for Recent Kinase

Inhibitors 101

4.3 Kinetics of Inhibition 103

4.3.1 ATP-Dependence 104

4.3.2 Rates of Onset and Reversal of Inhibition 105

4.3.3 Tight Binding Inhibition 1064.3.4 Binding Assays 107

4.3.5 Relationships Between IC50, Ki and Kd 109

4.4 Implications of Mechanisms and Kinetics 110

4.4.1 Identification and Evaluation of Inhibitors 110

4.4.2 Clinical Implications 114

4.5 Conclusions 120

Acknowledgements 121

References 121

Chapter 5 Kinase Mutations and Resistance in Cancer 126

Jack Andrew Bikker

5.1 Introduction 126

5.1.1 Kinase activation 129

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5.1.2 Type I, Type II and Type III inhibitors 131

5.1.3 Chapter overview 132

5.2 Kinases inhibited by imatinib 132

5.2.1 Resistance mutations to imatinib and successor

compounds (BCR-Abl) 133

5.2.2 Resistance mutations to imatinib and successor

compounds (Kit kinase) 1355.2.3 Design strategies to overcome resistance

mutations 136

5.3 EGFR kinases 139

5.3.1 Activating mutations leading to drug

susceptibility 139

5.3.2 EGFR resistance mutations 141

5.3.3 Inhibitors and design strategies 141

5.4 Preclinical prediction of kinase resistance mutations 1445.5 Resistance mechanisms not involving kinase domain

mutations 147

5.6 Outlook 151

References 153

Chapter 6 Non-Protein Kinases as Therapeutic Targets 161

Jeroen C. Verheijen, David J. Richard and Arie Zask

6.1 Introduction 161

6.2 Sugar Kinases 162

6.2.1 Hexokinases (HK) 162

6.2.2 Ketohexokinase (KHK, fructokinase) 163

6.2.3 6-Phosphofructo-2-kinase/Fructose-2,6-

bisphosphatase (PFK2/FBPase2) 163

6.2.4 Galactokinase 164

6.2.5 Conclusion 1646.3 Nucleoside Kinases 164

6.3.1 Uridine-cytidine Kinase 164

6.3.2 Thymidine Kinase 165

6.3.3 Deoxycytidine Kinase 166

6.3.4 Adenosine Kinase 167

6.3.5 Conclusion 172

6.4 Lipid kinases 173

6.4.1 PI3K and Structurally Related Kinases 1736.4.2 Other Phosphatidylinositol Kinases 193

6.4.3 Other Lipid Kinases 195

6.4.4 Conclusion 200

6.5 Other Non-Protein Kinases 200

6.5.1 Mevalonate Kinase 200

6.5.2 Pyruvate Kinase (PK) 201

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6.5.3 Pantothenate Kinase 202

6.6 Conclusion 202

6.7 Acknowledgement 203

References 203

Chapter 7 The Drug Discovery and Development of Kinase Inhibitors

Outside of Oncology 218A. J. Ratcliffe

7.1 Introduction 218

7.2 Inhibitors of Rho Kinane - fasudil 221

7.3 Inhibitors of p38a 222

7.4 Inhibitors of SYK 227

7.5 Inhibitors of PKC 229

7.6 Inhibitors of JAK 2307.7 Inhibitors of MAPKAPK5 236

7.8 Multikinase Inhibitors 236

7.9 Inhibitors of Bcr-Abl, c-Kit and PDGFR – imatinib

(gleevec) and nilotinib (tasigna) 237

7.10 Conclusion 239

References 239

Chapter 8 Allosteric Activators of Glucokinase (GK) for the Treatmentof Type 2 Diabetes 244

Kevin R. Guertin

8.1 Introduction 244

8.2 Glucokinase Structure and Function 245

8.3 The Initial Discovery of Small Molecule Glucokinase

Activators 247

8.4 Recent Advancements in the Identification of SmallMolecule GK Activators 250

8.4 Selected Novel Glucokinase Activator Structures from

Recent Patent Literatur 254

8.5 Conclusion 259

8.6 Acknowledgements 259

References 259

Chapter 9 Drug Discovery and Non-Human Kinomes 262Andrew F. Wilks and Isabelle Lucet

9.1 The Burden of Human Parasitic Diseases 262

9.2 Non-Human Kinomes 263

9.3 Kinetoplastids 264

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9.3.1 The Kinomes of Trypanosoma 265

9.4 Apicomplexa 265

9.4.1 Malaria 265

9.4.2 The Plasmodium Kinome 267

9.5 Drugability: Prospects for New Drugs 271

9.5.1 Will P. falciparum Kinase Inhibitors Work as

Anti-Malarial Drugs? 2719.5.2 Specificity & Safety 272

9.5.3 Prioritisation of Targets 272

9.6 Technical Challenges 275

9.6.1 Structural Biology 275

9.7 Chemical Biology and Drug Discovery Programmes 277

9.7.1 In Vitro Screening of Validated Plasmodium

Kinases 278

9.7.2 ‘‘Malaria Boxes’’ 2809.8 Summary 281

References 281

Chapter 10 The Future of Kinase Drug Discovery 286

Carlos Garcı́a-Echeverrı́a

10.1 Introduction 286

10.2 Overcoming resistance 28610.2.1 Irreversible kinase inhibitors 287

10.2.2 Optimizing target modulation and

pharmacological properties 290

10.2.3 Polypharmacological inhibitors and

combinations thereof 292

10.3 Magic bullets and new chemical space 295

10.4 Beyond kinase inhibitors 296

10.4.1 Kinase activation – a new paradigm in drugdiscovery 296

10.4.2 Pseudokinases – new kids on the block 297

10.5 Outlook 298

Acknowledgements 299

References 299

Subject Index 303

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