Table of Contents
Kinases: Highways to Drug Discovery Executive Summary 16
Chapter 1 Kinases as drug targets 16
Chapter 2 Small molecule kinase inhibitor discovery 17
Chapter 3 Targeting kinases in cancer 18
Chapter 4 Non-cancer applications of kinase drugs 20
Chapter 5 Leading kinase drug originating companies 21
Chapter 6 Market Analysis: Trends and Forecasts 22
Chapter 1 Kinases as drug targets 26
Summary 26
Introduction 27
Overview of human protein kinases 30
Classification schemes 32
Kinases in signal transduction pathways 36
MAPK pathways 38
MAPK (ERK) pathway 39
JNK/SAPK pathway 40
MAPK14 pathway 40
PI3K/AKT signaling 41
JAK/STAT signaling 41
NFKB pathway 42
Insulin receptor signaling 43
Immune cell signaling 43
T cell receptor signaling 43
B-cell receptor complexes 44
Signaling in vascular morphogenesis 44
VEGF receptor signaling 44
EGF receptor signaling 45
Cyclic nucleotide metabolism 45
Cell cycle checkpoint controls 45
Categories of kinase-targeted drugs 46
Small molecules 47
Monoclonal antibodies 49
Emerging biopharmaceuticals 50
Kinase drug audit 51
Chapter 2 Small molecule kinase inhibitor discovery 58
Summary 58
Introduction 59
Mechanisms of kinase inhibition 60
ATP competitive inhibitors 60
Irreversible inhibitors 61
Allosteric inhibitors 62
Approaches to kinase inhibitor discovery 63
Traditional kinase inhibitor discovery 63
High-throughput screening of compound libraries 63
Lead optimization 65
Synthesis of inhibitor analogs 65
Structure-informed drug design 66
Structure-informed drug re-design 67
Fragment-based drug discovery 68
Kinase inhibitor selectivity assays 69
Protein selectivity assays 70
Kinase activity assays 70
Kinase binding assays 71
Cellular selectivity assays 73
Identifying substrates of kinases 74
Chapter 3 Targeting kinases in cancer 78
Summary 78
Overview of cancer 79
Established and emerging therapies 84
Therapeutic potential of kinase inhibition 86
Types of kinase targets 89
Mutationally-activated kinases 89
Kinases which sustain tumor growth 90
Kinases with roles in tumorigenesis 91
Top 20 kinase targets 92
Group: TK 92
ABL1 (Abl family) 92
Target characteristics 92
Inhibitors on the market 93
Inhibitors in development 96
EGFR and ERBB2 (EGFR family) 101
Target characteristics 101
Approaches to EGFR inhibition 102
Inhibitors on the market 104
Inhibitors in development 107
FLT3, KIT, PDGFRA, and PDGFRB (PDGFR family) 117
Target characteristics 117
Inhibitors on the market 118
Inhibitors in development 119
FLT1, FLT4, and KDR (VEGFR family) 136
Target characteristics 136
Inhibitors on the market 137
Inhibitors in development 138
JAK2 (JakA family) 152
Target characteristics 152
Drugs in development 152
MET (Met family) 155
Target characteristics 155
Agents in development 155
Group: AGC 158
AKT1 (AKT family) 158
Target characteristics 158
Drugs in development 158
Group: CMGC 161
CDC2 and CDK2 (CDK family; CDC2 subfamily) 161
Target characteristics 161
Drugs in development 161
Group: Other 165
AURKA and AURKB (AUR family) 165
Target characteristics 165
Drugs in development 165
PLK1 (PLK family) 169
Target characteristics 169
Drugs in development 169
Group: Atypical 171
Target characteristics 171
Inhibitors on the market 171
Inhibitors in development 172
Dual specificity lipid/protein kinases 176
PIK3CA (PI3K) 176
Target characteristics 176
Inhibitors in development 177
Future trends 181
Chapter 4 Non-cancer applications of kinase drugs 184
Summary 184
Introduction 185
Chronic inflammation and kinases 185
Leading indications 187
Arthritis 187
Diabetes 195
Inflammation 201
Immunosuppression 205
Ophthalmology 208
Psoriasis 211
Pulmonary diseases 214
Cardiovascular 218
Myelodysplastic disorders 222
GI disorders 227
Pain 229
Leading kinase targets 231
MAPK14 231
Target characteristics 231
Inhibitors in development 232
FRAP1 233
Target characteristics 233
Inhibitors on the market 233
Inhibitors in development 234
JAK3 234
Target characteristics 234
Inhibitors in development 234
NTRK1 234
Target characteristics 234
Inhibitors in development 235
ROCK1 235
Target characteristics 235
Inhibitors on the market 235
Inhibitors in development 236
Chapter 5 Leading kinase drug originating companies 238
Summary/Introduction 238
5.1 Abbott Laboratories 239
Company overview 239
Kinase-related collaborations (2005 onwards) 239
Kinase drug pipeline 239
Ambit Biosciences Corp 241
Company overview 241
Kinase-related collaborations (2005 onwards) 241
Kinase drug pipeline 242
Amgen Inc 244
Company overview 244
Kinase-related collaborations (2005 onwards) 244
Kinase drug pipeline 244
Array BioPharma Inc 246
Company overview 246
Kinase-related collaborations (2005 onwards) 246
Kinase drug pipeline 246
AstraZeneca plc 248
Company overview 248
Kinase-related collaborations (2005 onwards) 248
Kinase drug pipeline 249
Avila Therapeutics Inc 251
Company overview 251
Kinase drug pipeline 252
Boehringer Ingelheim GmbH 253
Company overview 253
Kinase-related collaborations (2005 onwards) 253
Kinase drug pipeline 254
Bristol-Myers Squibb Co 256
Company overview 256
Kinase-related collaborations (2005 onwards) 256
Kinase drug pipeline 257
Cephalon Inc 259
Company overview 259
Kinase-related collaborations (2005 onwards) 259
Kinase drug pipeline 259
Deciphera Pharmaceuticals LLC 261
Company overview 261
Kinase-related collaborations (2005 onwards) 261
Kinase drug pipeline 261
Eli Lilly Co 263
Company overview 263
Kinase-related collaborations (2005 onwards) 263
Kinase drug pipeline 264
Exelixis Inc 268
Company overview 268
Kinase-related collaborations (2005 onwards) 268
Kinase drug pipeline 269
GlaxoSmithKline plc 271
Company overview 271
Kinase-related collaborations (2005 onwards) 271
Kinase drug pipeline 272
Hoffmann-La Roche Ltd 274
Company overview 274
Kinase-related collaborations (2005 onwards) 274
Kinase drug pipeline 275
Johnson & Johnson 277
Company overview 277
Kinase-related collaborations (2005 onwards) 277
Kinase drug pipeline 278
Kyowa Hakko Kirin Co Ltd 280
Company overview 280
Kinase-related collaborations (2005 onwards) 280
Kinase drug pipeline 280
Novartis International AG 282
Company overview 282
Kinase-related collaborations (2005 onwards) 282
Kinase drug pipeline 283
Pfizer Inc 286
Company overview 286
Kinase-related collaborations (2005 onwards) 287
Kinase drug pipeline 287
Sanofi-Aventis Group 289
Company overview 289
Kinase drug pipeline 289
Wyeth 291
Company overview 291
Kinase-related collaborations (2005 onwards) 291
Kinase drug pipeline 292
Chapter 6 Market Analysis: Trends and Forecasts 296
Summary 296
Prevalence of targeted diseases 297
Analyses and Forecasts by Type of Agent 299
Limus agents/mTOR inhibitors 303
Overview 303
Standalone mTOR inhibitors 304
Drug-eluting stents 305
Drug-eluting stent market 306
Sirolimus-eluting stents 307
Everolimus- and zotarolimus-eluting stents 307
Sales trends in mTOR inhibitors 308
Forthcoming mTOR inhibitors 308
EGFR Family inhibitors 309
Overview 309
Trastuzumab 309
Erlotinib 310
Cetuximab 310
Gefitinib 311
Panitumumab 311
Lapatinib 311
Nimotuzumab 312
Sales trends in EGFR Family inhibitors 312
Forthcoming EGFR Family Inhibitors 313
ABL/FLT3 Group Inhibitors 313
Overview 313
Imatinib 314
Dasatinib 314
Nilotinib 315
Sales trends in ABL1/FLT3 Family Inhibitors 315
Forthcoming ABL1/FLT3 Family Inhibitors 315
VEGFR Family 316
Overview 316
Sunitinib 317
Sorafenib 317
Sales trends in VEGFR Family inhibitors 317
Forthcoming VEGFR Family Inhibitors 318
Other launched agents 318
Overview 318
Fasudil 319
Pirfenidone 319
Sales trends of other agents 319
Other forthcoming agents 320
Company sales and trends 321
Patenting trends 323
Appendix 1 Kinase-related targets and their abbreviations 326
Appendix 2 Other abbreviations and acronyms 329
Appendix 3 Research Methodology 331
Index 332
List of Figures
Figure 1.1: Leading kinase-targeted drug applications 53
Figure 1.2: Kinase target landscape 54
Figure 6.3: Kinase originator market shares 323
List of Tables
Table 1.1: Human Kinase Gene Audit 29
Table 1.2: Hanks Classification of Protein Kinases (1995) 34
Table 1.3: Hanks Classification of Protein Kinases (1995) (continued) 35
Table 1.4: Kinase Agents by Development Stage 52
Table 1.5: Kinase Drugs by Product Type 52
Table 1.6: Leading developers of therapeutic kinase-targeted drugs 53
Table 1.7: Kinase Agonists and Stimulants 55
Table 3.8: Kinases implicated in human cancer 82
Table 3.9: Kinases implicated in human cancer (continued) 83
Table 3.10: Top 20 Kinase Targets in Cancer 90
Table 3.11: Overview of ABL1-targeted agents in cancer 98
Table 3.12: Overview of ABL1-targeted agents in cancer (continued 1) 99
Table 3.13: Overview of ABL1-targeted agents in cancer (continued 2) 100
Table 3.14: Overview of EGFR-targeted agents in cancer 109
Table 3.15: Overview of EGFR-targeted agents in cancer (Phase III and above) 110
Table 3.16: Overview of EGFR-targeted agents in cancer (Phase II) 111
Table 3.17: Overview of EGFR-targeted agents in cancer (Phase I) 112
Table 3.18: Overview of EGFR-targeted agents in cancer (Preclinical) 113
Table 3.19: Overview of ERBB2-targeted agents in cancer (Phase III and above) 114
Table 3.20: Overview of ERBB2-targeted agents in cancer (Phase II) 115
Table 3.21: Overview of ERBB2-targeted agents in cancer (Phase I and Preclinical) 116
Table 3.22: Overview of FLT3-targeted agents in cancer (Launched) 120
Table 3.23: Overview of FLT3-targeted agents in cancer (Phase II and III) 121
Table 3.24: Overview of FLT3-targeted agents in cancer (Phase I and II) 122
Table 3.25: Overview of FLT3-targeted agents in cancer (Preclinical and Phase I) 123
Table 3.26: Overview of KIT-targeted agents in cancer 124
Table 3.27: Overview of KIT-targeted agents in cancer (Continued 1) 125
Table 3.28: Overview of KIT-targeted agents in cancer (Continued 2) 126
Table 3.29: Overview of KIT-targeted agents in cancer (Continued 3) 127
Table 3.30: Overview of KIT-targeted agents in cancer (Continued 4) 128
Table 3.31: Overview of KIT-targeted agents in cancer (Continued 4) 129
Table 3.32: Overview of PDGFRA-targeted agents in cancer 130
Table 3.33: Overview of PDGFRA-targeted agents in cancer (Continued 1) 131
Table 3.34: Overview of PDGFRA-targeted agents in cancer (Continued 2) 132
Table 3.35: Overview of PDGFRA-targeted agents in cancer (Continued 3) 133
Table 3.36: Overview of PDGFRB-targeted agents in cancer (Phase II and Phase III) 134
Table 3.37: Overview of PDGFRB-targeted agents in cancer (Preclinical and Phase I) 135
Table 3.38: Overview of FLT1-targeted agents in cancer 139
Table 3.39: Overview of FLT1-targeted agents in cancer (Continued 1) 140
Table 3.40: Overview of FLT1-targeted agents in cancer (Continued 2) 141
Table 3.41: Overview of FLT1-targeted agents in cancer (Continued 3) 142
Table 3.42: Overview of FLT4-targeted agents in cancer 143
Table 3.43: Overview of FLT4-targeted agents in cancer (Continued 1) 144
Table 3.44: Overview of FLT4-targeted agents in cancer (Continued 2) 145
Table 3.45: Overview of KDR-targeted agents in cancer 146
Table 3.46: Overview of KDR-targeted agents in cancer (Continued 1) 147
Table 3.47: Overview of KDR-targeted agents in cancer (Continued 2) 148
Table 3.48: Overview of KDR-targeted agents in cancer (Continued 3) 149
Table 3.49: Overview of KDR-targeted agents in cancer (Continued 4) 150
Table 3.50: Overview of KDR-targeted agents in cancer (Continued 5) 151
Table 3.51: Overview of JAK2-Targeted Agents in Cancer 153
Table 3.52: Overview of JAK2-Targeted Agents in Cancer (continued) 154
Table 3.53: Overview of MET-Targeted Agents in Cancer (continued) 156
Table 3.54: Overview of MET-Targeted Agents in Cancer (continued) 157
Table 3.55: Overview of AKT1-Targeted Agents in Cancer (continued) 159
Table 3.56: Overview of AKT1-Targeted Agents in Cancer (continued) 160
Table 3.57: Overview of CDC2-Targeted Agents in Cancer 162
Table 3.58: Overview of CDK2-Targeted Agents in Cancer 163
Table 3.59: Overview of CDK2-Targeted Agents in Cancer (continued) 164
Table 3.60: Overview of AURKA-Targeted Agents in Cancer 166
Table 3.61: Overview of AURKA -Targeted Agents in Cancer (continued) 167
Table 3.62: Overview of AURKB -Targeted Agents in Cancer 168
Table 3.63: Overview of PLK1 -Targeted Agents in Cancer 170
Table 3.64: Overview of FRAP1 -Targeted Agents in Cancer 173
Table 3.65: Overview of FRAP1 -Targeted Agents in Cancer (Continued 1) 174
Table 3.66: Overview of FRAP1 -Targeted Agents in Cancer (Continued 2) 175
Table 3.67: Overview of PIK3CA -Targeted Agents in Cancer 179
Table 3.68: Overview of PIK3CA -Targeted Agents in Cancer (Continued) 180
Table 4.69: Kinase-Targeted Agents With Anti-Arthritic Applications 188
Table 4.70: Kinase-Targeted Agents With Anti-Arthritic Applications (continued 1) 189
Table 4.71: Kinase-Targeted Agents With Anti-Arthritic Applications (continued 2) 190
Table 4.72: Kinase-Targeted Agents With Anti-Arthritic Applications (continued 3) 191
Table 4.73: Kinase-Targeted Agents With Anti-Arthritic Applications (continued 4) 192
Table 4.74: Kinase-Targeted Agents With Anti-Arthritic Applications (continued 5) 193
Table 4.75: Kinase-Targeted Agents With Diabetes Applications 198
Table 4.76: Kinase-Targeted Agents With Diabetes Applications (continued 1) 199
Table 4.77: Kinase-Targeted Agents With Diabetes Applications (continued 2) 200
Table 4.78: Kinase-Targeted Agents With Inflammatory Applications 202
Table 4.79: Kinase-Targeted Agents With Inflammatory Applications (Continued 1) 203
Table 4.80: Kinase-Targeted Agents With Inflammatory Applications (Continued 2) 204
Table 4.81: Kinase-Targeted Agents With Immunosuppresive Applications 206
Table 4.82: Kinase-Targeted Agents With Immunosuppresive Applications (continued) 207
Table 4.83: Kinase-Targeted Agents With Ophthalmological Applications 209
Table 4.84: Kinase-Targeted Agents With Ophthalmological Applications (continued) 210
Table 4.85: Kinase-Targeted Agents With Psoriasis Applications (continued) 212
Table 4.86: Kinase-Targeted Agents With Psoriasis Applications (continued) 213
Table 4.87: Kinase-Targeted Agents With PulmonaryApplications (Launched) 215
Table 4.88: Kinase-Targeted Agents With PulmonaryApplications (Phase I-III) 216
Table 4.89: Kinase-Targeted Agents With PulmonaryApplications (Preclinical) 217
Table 4.90: Kinase-targeted agents with cardiovascular applications 220
Table 4.91: Kinase-targeted agents with cardiovascular applications (continued) 221
Table 4.92: Kinase-targeted agents with myelodysplastic disorder applications 223
Table 4.93: Kinase-targeted agents with myelodysplastic disorder applications (continued) 224
Table 4.94: Kinase-targeted agents with myelodysplastic disorder applications (continued 2) 225
Table 4.95: Kinase-targeted agents with myelodysplastic disorder applications (continued 3) 226
Table 4.96: Kinase-targeted agents with GI disorder applications 228
Table 4.97: Kinase-targeted agents with GI disorder applications 230
Table 5.98: Overview of Abbott's kinase pipeline by status 240
Table 5.99: Overview of Ambit Biosciences' Kinase Pipeline by Status 243
Table 5.100: Overview of Amgen's kinase pipeline by status 245
Table 5.101: Overview of Array BioPharma's kinase pipeline by status 247
Table 5.102: Overview of AstraZeneca’s kinase pipeline by status 250
Table 5.103: Overview of Avila Therapeutics' kinase pipeline by status 252
Table 5.104: Overview of Boehringer Ingelheim's kinase pipeline by status 255
Table 5.105: Overview of Bristol-Myers Squibb's (BMS) kinase pipeline by status 258
Table 5.106: Overview of Cephalon's kinase pipeline by status 260
Table 5.107: Overview of Deciphera Pharmaceuticals' kinase pipeline by status 262
Table 5.108: Overview of Eli Lilly’s kinase pipeline by status 266
Table 5.109: Overview of Eli Lilly’s kinase pipeline by status (continued) 267
Table 5.110: Overview of Exelixis’ kinase pipeline by status 270
Table 5.111: Overview of Exelixis’ kinase pipeline by status 273
Table 5.112: Overview of Hoffmann-La Roche's kinase pipeline by status 276
Table 5.113: Overview of Johnson & Johnson's kinase pipeline by status 279
Table 5.114: Overview of Kyowa Hakko Kirin's kinase pipeline by status 281
Table 5.115: Overview of Novartis’ kinase pipeline by status 284
Table 5.116: Overview of Novartis’ kinase pipeline by status (continued) 285
Table 5.117: Overview of Pfizer’s kinase pipeline by status 288
Table 5.118: Overview of Sanofi-Aventis' kinase pipeline by status 290
Table 5.119: Overview of Wyeth’s kinase pipeline by status 293
Table 6.120: World Prevalence Of Diseases 297
Table 6.121: World Pharma Market by Indication (US$m), 2008-2013 300
Table 6.122: World Pharma Market by Region (US$m), 2008-2013 301
Table 6.123: Kinase Drug Analysis (in 2007-2008) and Forecasts, 2009-2013 ($USm) 302
Table 6.124: Kinase Inhibitors by Geography ($USm), 2008 and 2013 303
Table 6.125: Manufacturer Analysis (2008) and Forecasts (US$m), 2009-2013 322
Table 6.126: Major Kinase Patent Indications 324
Table 6.127: Leading Kinase Patent Assignees 325