Target Validation in Drug Discovery (eBook)

Front Cover 1
Title Page 4
Copyright Page 5
Table of Contents 6
Preface 8
Contributors 12
PART I PHARMACEUTICAL BIOTECHNOLOGY FOR TARGET VALIDATION 14
Chapter 1 Generation of Transgenic Animals 16
I. INTRODUCTION 16
II. GENERATION OF TRANSGENIC ANIMALS FOR TARGET VALIDATION 17
III. CONCLUSION 36
ACKNOWLEDGMENTS 36
RECOMMENDED RESOURCES 37
REFERENCES 37
Chapter 2 Target Validation in Chemogenomics 40
I. INTRODUCTION 40
II. REVERSE CHEMOGENOMICS: TARGET VALIDATION USING COMPOUNDS WITH KNOWN MOLECULAR TARGET (AND/OR MECHANISM OF ACTION) 41
III. FORWARD CHEMOGENOMICS: TARGET IDENTIFICATION/VALIDATION USING COMPOUNDS WITH UNKNOWN MECHANISM OF ACTION 46
IV. CONCLUSION 50
REFERENCES 50
PART II TARGET VALIDATION FOR BIOPHARMACEUTICAL DRUG DISCOVERY 54
Chapter 3 Cetuximab (Erbitux®), An Anti-Epidermal Growth Factor Receptor Antibody for the Treatment of Metastatic Colorectal Cancer 56
I. INTRODUCTION 56
II. EPIDERMAL GROWTH FACTOR RECEPTOR AND ITS ROLE IN HUMAN CANCER 58
III. CETUXIMAB (ERBITUX®, IMC-C225) 59
IV. CETUXIMAB IN CLINICAL STUDIES IN PATIENTS WITH mCRC 62
V. MECHANISMS OF ACTION OF CETUXIMAB 64
VI. CONCLUSIONS AND PERSPECTIVES 67
RECOMMENDED RESOURCES 72
REFERENCES 73
Chapter 4 Monoclonal Antibody to HER-2 in Breast Cancer 82
I. INTRODUCTION 82
II. MECHANISM OF ACTION OF TRASTUZUMAB 83
III. MOLECULAR MECHANISMS OF TRASTUZUMAB RESISTANCE 86
IV. ASSESSMENT OF HER-2 STATUS 87
V. CLINICAL TRIALS WITH TRASTUZUMAB 89
CONCLUSION 91
ACKNOWLEDGMENTS 91
USEFUL WEBSITES 92
REFERENCES 92
Chapter 5 Validation of TNF as a Drug Target in Inflammatory Bowel Disease 96
I. INTRODUCTION 97
II. TUMOR NECROSIS FACTOR 97
III. INFLAMMATORY BOWEL DISEASE 98
IV. PATHOPHYSIOLOGY OF IBD AND THE PUTATIVE ROLE OF TNF 100
V. CLINICAL EXPERIENCE WITH TNF-BLOCKING THERAPY IN IBD 104
CONCLUSION 112
ACKNOWLEDGMENTS 112
REFERENCES 112
Chapter 6 Anti–CCL-2/MCP-1: Directed Biologicals for Inflammatory and Malignant Diseases 116
I. INTRODUCTION 116
II. IN VITRO ASSAYS TO ESTABLISH THE PRO-INFLAMMATORY ACTIVITIES OF CCL-2 118
III. IN VIVO VALIDATION STUDIES 122
IV. SUMMARY 126
ACKNOWLEDGMENTS 127
REFERENCES 127
Chapter 7 Targeting IL-12p40 for Immune-Mediated Disease 134
I. INTRODUCTION 134
II. IN VITRO TARGET VALIDATION OF IL-12p40 135
III. IN VIVO PROOF-OF-CONCEPT FOR IL-12p40 INHIBITION 139
IV. CONCLUSION 143
RECOMMENDED RESOURCES 144
REFERENCES 144
Chapter 8 The GPIIb/IIIa Antagonist Abciximab for Acute Percutaneous Coronary Intervention 148
I. INTRODUCTION 148
II. RATIONALE FOR GPIIb/IIIa AS A TARGET IN CORONARY ARTERIAL DISEASE 149
III. GENERATION OF THE 7E3 MONOCLONAL ANTIBODY AGAINST GPIIb/IIIa 150
IV. IN VITRO STUDIES 150
V. ANIMAL STUDIES 154
VI. PLATELET PHARMACODYNAMIC PHENOMENA RECOGNIZED LATER 156
VII. CROSS REACTIVITY WITH OTHER INTEGRINS 158
VIII. INTEGRATION OF CLINICAL PHARMACOLOGY AND PRECLINICAL STUDIES 159
IX. CLINICAL STUDIES 160
X. CONCLUSION 162
RECOMMENDED RESOURCES 162
REFERENCES 162
PART III VALIDATING TARGETS OF SMALL MOLECULE APPROACHES 166
Chapter 9 Epidermal Growth Factor Receptor (EGFR) Inhibitor for Oncology: Discovery and Development of Erlotinib 168
I. INTRODUCTION 168
II. EPIDERMAL GROWTH FACTOR RECEPTOR AND LIGANDS 169
III. DISCOVERY OF AN EGFR INHIBITOR FOR DRUG DEVELOPMENT 177
IV. CONCLUSIONS 186
RECOMMENDED RESOURCES 186
REFERENCES 187
Chapter 10 Progress in Achieving Proof of Concept for p38 Kinase Inhibitors 192
I. INTRODUCTION 192
II. INHIBITORS 196
III. CLINICAL STATUS 207
IV. CONCLUSION 208
REFERENCES 209
Chapter 11 IKK-2/NF-kappa B–Dependent Transcription 212
I. INTRODUCTION 212
II. BIOLOGICAL ROLES OF NF-kappa B 213
III. ENZYMOLOGY 218
IV. IKK INHIBITORS 219
V. DISCUSSION/MECHANISM-BASED TOXICITY 226
VI. CONCLUSIONS AND OUTLOOK 228
RECOMMENDED OTHER READING 229
REFERENCES 230
Chapter 12 TNF Signaling Pathway Inhibitors for Inflammation-CCR2 Antagonists 236
I. INTRODUCTION 236
II. MACROPHAGES IN RHEUMATOID ARTHRITIS 238
III. MACROPHAGES IN MULTIPLE SCLEROSIS 239
IV. MACROPHAGES IN ATHEROSCLEROSIS 241
V. MACROPHAGES IN METABOLIC SYNDROME 242
VI. CCR2 ANTAGONISM AS A NEW APPROACH TO MODULATE INFLAMMATION 244
VII. CCR2 ANTAGONISM IN ARTHRITIS 244
VIII. CCR2 AND MULTIPLE SCLEROSIS 245
IX. CCR2 AND ATHEROSCLEROSIS 246
X. CCR2 AND DIABETES 248
XI. CONCLUDING REMARKS 248
RECOMMENDED RESOURCES 249
REFERENCES 250
Chapter 13 The Discovery of Eltrombopag, An Orally Bioavailable TpoR Agonist 254
I. THROMBOCYTOPENIA AND MEGAKARYOCYTOPOIESIS 255
II. THE DISCOVERY OF SMALL-MOLECULE TpoR AGONISTS AT GLAXOSMITHKLINE 257
CONCLUSIONS 265
ACKNOWLEDGMENTS 265
REFERENCES 266
Chapter 14 Orally Bioavailable Glycoprotein IIb/IIIa Antagonists: A Negative Case Study 268
I. INTRODUCTION 268
II. ROLE OF GP IIb/IIIa IN PLATELET BIOLOGY: CLUES FOR TARGET VALIDATION? 269
III. PHARMACOLOGY OF ORALLY BIOAVAILABLE GP IIb/IIIa ANTAGONISTS 272
IV. KEY RESULTS FROM PHASE III STUDIES 277
V. LACK OF EXPLANATION FOR EXCESS MORTALITY IN LARGE PHASE III TRIALS 278
CONCLUSIONS AND LESSONS LEARNED 280
REFERENCES 280
INDEX 282