| Preface |
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xi | |
| Acknowledgments |
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xiii | |
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1 | (74) |
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A Brief History of Protein Phosphorylation |
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1 | (2) |
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3 | (5) |
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A Tour of the Human Protein Kinase Superfamily |
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8 | (38) |
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12 | (10) |
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TKL (Tyrosine Kinase-like) Group |
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22 | (3) |
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25 | (2) |
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27 | (1) |
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28 | (2) |
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30 | (2) |
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32 | (4) |
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36 | (1) |
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36 | (5) |
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41 | (1) |
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41 | (5) |
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Strategic Considerations for Selecting Kinases as Drug Targets |
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46 | (5) |
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Comparison of Kinase Inhibitor Therapeutic Strategies |
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51 | (7) |
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Small Molecule Versus Antibody-Directed Therapies |
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51 | (1) |
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Alternative Strategies for Kinase Inhibition |
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51 | (7) |
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58 | (17) |
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Protein Kinase Structure, Function, and Regulation |
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75 | (44) |
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Ligand Binding to Receptor Tyrosine Kinases |
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76 | (7) |
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EGF: EGF Receptor Interactions |
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76 | (2) |
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Insulin: Insulin Receptor and IGF1: IGF1R |
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78 | (1) |
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FGF: FGF Receptor (Heparin/Heparan Sulfate) Interactions |
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79 | (1) |
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VEGF: VEGF Receptor Interactions |
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80 | (1) |
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Angiopoietin2: TIE2 Receptor Interactions |
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80 | (2) |
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Ephrin: EPH Receptor Interactions |
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82 | (1) |
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The Role of Transmembrane Domains |
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82 | (1) |
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Protein Kinase Domain Structure and Function |
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83 | (4) |
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Catalytic Activity of Protein Kinases |
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87 | (4) |
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87 | (2) |
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Chemistry of Protein Kinase Catalysis |
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89 | (2) |
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Protein Kinase Regulation |
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91 | (16) |
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Regulation Via Activation Segment Phosphorylation |
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92 | (4) |
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Regulation by N-Terminal Sequences and Domains |
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96 | (2) |
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C-Terminal Regulatory Regions |
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98 | (4) |
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Regulation by Other Domains and Partner Proteins |
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102 | (5) |
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107 | (12) |
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Receptor Tyrosine Kinases |
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119 | (96) |
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120 | (10) |
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ERBB Receptors and Cancer |
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128 | (2) |
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130 | (6) |
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Insulin/IGF Receptors and Cancer |
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134 | (2) |
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Anaplastic Lymphoma Kinase |
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136 | (4) |
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137 | (3) |
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VEGF Receptors (VEGFR1, VEGFR2, VEGFR3) |
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140 | (6) |
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146 | (7) |
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149 | (4) |
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153 | (5) |
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156 | (2) |
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158 | (7) |
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160 | (5) |
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165 | (3) |
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167 | (1) |
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168 | (2) |
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RET and Thyroid Carcinoma |
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169 | (1) |
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170 | (7) |
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170 | (5) |
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175 | (2) |
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177 | (38) |
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Nonreceptor Tyrosine Kinases |
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215 | (50) |
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216 | (7) |
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223 | (1) |
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SRC and SRC Family Kinases |
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224 | (11) |
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228 | (4) |
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232 | (2) |
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234 | (1) |
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235 | (3) |
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238 | (1) |
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238 | (8) |
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Activation and Known Mutations and Fusions of the JAK Family of Tyrosine Kinases |
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241 | (2) |
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Further Roles of JAK2 in Tumor Growth |
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243 | (3) |
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246 | (19) |
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Intracellular Signal Transduction Cascades |
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265 | (62) |
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266 | (13) |
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267 | (3) |
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270 | (1) |
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271 | (2) |
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273 | (2) |
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PI3K Pathway Activation in Cancer |
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275 | (4) |
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279 | (5) |
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279 | (3) |
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282 | (1) |
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mTOR Pathway Activation in Cancer |
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283 | (1) |
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284 | (9) |
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285 | (1) |
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286 | (3) |
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289 | (2) |
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ERK/MAPK Pathway Activation in Cancer |
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291 | (2) |
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293 | (1) |
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294 | (7) |
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295 | (3) |
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298 | (1) |
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299 | (1) |
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300 | (1) |
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301 | (26) |
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327 | (64) |
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Cyclin-Dependent Kinases (CDKs) and Cell Cycle Progression |
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327 | (15) |
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328 | (4) |
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332 | (2) |
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334 | (3) |
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337 | (1) |
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337 | (4) |
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341 | (1) |
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341 | (1) |
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342 | (10) |
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342 | (2) |
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344 | (2) |
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346 | (1) |
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347 | (2) |
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349 | (1) |
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CDK12 (CDC2-Related Kinase CRKRS) |
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350 | (1) |
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351 | (1) |
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Other CDK-Related Kinases |
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352 | (2) |
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352 | (1) |
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353 | (1) |
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354 | (7) |
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356 | (3) |
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359 | (2) |
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Cell Cycle Checkpoint Kinases |
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361 | (7) |
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362 | (2) |
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364 | (4) |
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368 | (23) |
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Structural Biochemistry of Kinase Inhibitors |
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391 | (44) |
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Strategies for Inhibitor Design |
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392 | (4) |
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Targeting the Active Versus Inactive Form |
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392 | (1) |
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ATP-Competitive Versus Noncompetitive Inhibitors |
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393 | (1) |
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Specific Versus Multitargeted Inhibitors |
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394 | (2) |
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Architecture of the ATP Binding Site: DFG-in |
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396 | (3) |
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Case Study: Inhibitors of CHK1 |
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399 | (8) |
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Case Study: Inhibitors of CDK2 |
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407 | (6) |
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Case Study: Inhibitors of SRC Family Kinases |
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413 | (3) |
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Case Study: EGF Receptor Inhibitors |
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416 | (4) |
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Targeting the Inactive Conformation |
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420 | (4) |
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421 | (2) |
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Binding of BAY-43-9006 (Sorafenib) to the Inactive BRAF Kinase |
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423 | (1) |
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Noncompetitive Inhibition |
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424 | (2) |
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Kinase Inhibitor Specificity |
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426 | (3) |
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429 | (6) |
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Tyrosine Kinase Inhibitors |
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435 | (92) |
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435 | (11) |
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446 | (2) |
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448 | (4) |
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452 | (18) |
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Determinants of Response and Resistance to ERBB Inhibitors |
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455 | (15) |
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470 | (2) |
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472 | (8) |
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480 | (10) |
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490 | (6) |
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496 | (2) |
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498 | (2) |
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498 | (1) |
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499 | (1) |
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500 | (27) |
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527 | (40) |
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527 | (3) |
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530 | (25) |
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555 | (12) |
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Intracellular Signaling Kinase Inhibitors |
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567 | (56) |
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567 | (11) |
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Clinical Pharmacodynamics and Tolerability of mTOR Inhibitors |
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569 | (9) |
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578 | (4) |
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582 | (2) |
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584 | (3) |
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587 | (6) |
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Cell Cycle Checkpoint Kinase Inhibitors |
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593 | (4) |
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Mitotic Kinase Inhibitors |
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597 | (7) |
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597 | (2) |
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599 | (5) |
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Protein Kinase C Inhibitors |
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604 | (1) |
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605 | (18) |
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Current Challenges and Future Directions |
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623 | (42) |
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Kinase Inhibitor Drug Resistance |
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623 | (12) |
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Efflux Pumps and Drug Transporters |
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626 | (1) |
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627 | (1) |
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628 | (3) |
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Target Overexpression and Activation |
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631 | (1) |
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Downstream Pathway Activation |
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632 | (1) |
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Redundant Receptors/Pathways |
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633 | (2) |
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Combination Therapy With Kinase Inhibitors |
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635 | (6) |
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Angiogenesis Inhibitors and Chemotherapy |
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637 | (1) |
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Survival Pathway Inhibitors and Chemotherapy/Targeted Therapy |
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638 | (1) |
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DNA Damage Checkpoint Inhibitors and Chemotherapy |
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639 | (1) |
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RTK Switching: Targeting Receptor Redundancy |
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640 | (1) |
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Systems Biology and Translational Medicine |
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641 | (11) |
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Classification of Tumors and Prediction of Response: Expression Profiling |
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642 | (3) |
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Phosphoprotein Analysis, Kinomics, and Systems-Based Approaches |
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645 | (2) |
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647 | (5) |
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652 | (1) |
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653 | (12) |
| List of Abbreviations |
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665 | (24) |
| Index |
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689 | |