Kinase Inhibitors for Cancer

A A Mortlock and A J Barker, AstraZeneca, Macclesfield, UK © 2007 Elsevier Ltd. All Rights Reserved.

7.08.1 The Challenge of Cancer 184

7.08.2 The Basis of the Disease and the Role of Kinases 184

7.08.2.1 Signal Transduction and Cancer 184

7.08.2.2 Receptor Tyrosine Kinases (RTKs) 185

7.08.2.3 Cytoplasmic and Nuclear Kinases 185

7.08.3 The Human Kinome 187

7.08.4 Clinical Trial Issues 187

7.08.5 Tyrosine Kinases and their Inhibitors 188

7.08.5.1 Nonreceptor Tyrosine Kinases 188

7.08.5.2 Bcr-Abl 188

7.08.5.2.1 Bcr-Abl and cancer 188

7.08.5.2.2 Inhibitors of Bcr-Abl 189

7.08.5.2.3 Mechanistic understanding of imatinib 189

7.08.5.2.4 Bcr-Abl inhibitors in the clinic 189

7.08.5.2.5 Future directions 190

7.08.5.3 Src Family Kinases 190

7.08.5.3.1 Src family kinases in cancer 190

7.08.5.3.2 Src family kinase inhibitors 191

7.08.5.4 Receptor Tyrosine Kinases 192

7.08.5.5 Erb Family Tyrosine Kinase 193

7.08.5.5.1 Epidermal growth factor receptor tyrosine kinase in cancer 193

7.08.5.5.2 Inhibitors of epidermal growth factor receptor tyrosine kinase 193

7.08.5.5.3 Structural and mechanistic understanding of epidermal growth factor receptor 194

7.08.5.5.4 Epidermal growth factor receptor mutations 194

7.08.5.5.5 Epidermal growth factor receptor tyrosine kinase inhibitors in the clinic 194

7.08.5.5.6 ErbB2 and cancer 195

7.08.5.5.7 Inhibitors of ErbB2 195

7.08.5.5.8 Structural and mechanistic understanding of ErbB2 196

7.08.5.5.9 Future directions 197

7.08.5.6 Insulin-Like Growth Factor-1 Receptor (IGF-1R) 197

7.08.5.6.1 Insulin-like growth factor-1 receptor and cancer 197

7.08.5.6.2 Inhibitors of insulin-like growth factor-1 receptor 197

7.08.5.7 Type III Receptor Tyrosine Kinases (Platelet-Derived Growth Factor Receptor a, Platelet-Derived Growth Factor Receptor b, Colony Stimulating Factor 1R (CSF-1R), c-Kit, and Fms-Like Tyrosine Kinase (Flt3)) 197

7.08.5.7.1 Type III receptor tyrosine kinases and cancer 197

7.08.5.7.2 Type III receptor tyrosine kinase inhibitors 198

7.08.5.7.3 Type III receptor tyrosine kinases in the clinic 199

7.08.5.7.4 Future directions 199

7.08.5.8 Vascular Endothelial Growth Factor Receptor 200

7.08.5.8.1 Vascular endothelial growth factor receptor and cancer 200

7.08.5.8.2 Biopharmaceutical vascular endothelial growth factor inhibitors in the clinic 200

7.08.5.8.3 Small-molecule inhibitors of vascular endothelial growth factor receptor 200

7.08.5.8.4 Small-molecule vascular endothelial growth factor receptor inhibitors in the clinic 201

7.08.5.8.5 Future directions 201

7.08.5.9 Fibroblast Growth Factor Receptor (FGFR) 202

7.08.5.9.1 Fibroblast growth factor receptor and cancer 202

7.08.5.9.2 Fibroblast growth factor receptor inhibitors 203

7.08.6 Serine/Threonine Kinases 203

7.08.6.1 Serine/Threonine Kinases and Cancer 203

7.08.6.2 Mitogen-Activated Protein Kinase/Extracellular Signal-Related Kinase

Kinase (MEK) (MEK1 and MEK2) 203

7.08.6.2.1 Mitogen-activated protein kinase/extracellular signal-related kinase kinase and cancer 203

7.08.6.2.2 Inhibitors of mitogen-activated protein kinase/extracellular signal-related kinase kinase 204

7.08.6.2.3 Structural studies 205

7.08.6.2.4 Future directions 205

7.08.6.3 Cyclin-Dependent Kinases 205

7.08.6.3.1 Cyclin-dependent kinases and cancer 205

7.08.6.3.2 Cyclin-dependent kinase inhibitors 205

7.08.6.3.3 Cyclin-dependent kinase inhibitors in the clinic 207

7.08.6.3.4 Future directions 207

7.08.6.4 Aurora Family Kinases 207

7.08.6.4.1 Aurora kinases and cancer 207

7.08.6.4.2 Aurora kinase inhibitors 207

7.08.6.5 Raf Kinase 208

7.08.6.5.1 Raf and cancer 208

7.08.6.5.2 Inhibitors of Raf 208

7.08.6.6 Akt/3-Phosphoinositide-Dependent Kinase 1 (PDK1) 208

7.08.6.6.1 Akt/3-phosphoinositide-dependent kinase 1 and cancer 208

7.08.6.6.2 Inhibitors of Akt/3-phosphoinositide-dependent kinase 1 209

7.08.6.7 Protein Kinase C 209

7.08.6.7.1 Protein kinase C and cancer 209

7.08.6.7.2 Inhibitors of protein kinase C 209

7.08.7 Summary and Future Directions 210 References 210

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