Metcalf / Dillon Target Validation in Drug Discovery

1. Auflage 2011
ISBN: 978-0-08-046597-5
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 296 Seiten

This work presents a comprehensive contemporary framework for approaching target validation in drug discovery. It begins with a detailed description of new enabling technologies, including aptamers, RNA interference, functional genomics, and proteomics. The next section looks at biologic drug development with in-depth discussion of lessons learned from such well-known cases as Erbitux, Herceptin, and Avastin. Additional targets known as 'second generation' drugs, which can be identified when disease pathways are validated by biologics, present new possible small molecule therapeutics and serve as the focus of the final section of the book.

Autoren/Hrsg.

Metcalf, Brian W.

Dillon, Susan

Inhaltsverzeichnis

1;Front Cover;1
2;Title Page;4
3;Copyright Page;5
4;Table of Contents;6
5;Preface;8
6;Contributors;12
7;PART I PHARMACEUTICAL BIOTECHNOLOGY FOR TARGET VALIDATION;14
7.1;Chapter 1 Generation of Transgenic Animals;16
7.1.1;I. INTRODUCTION;16
7.1.2;II. GENERATION OF TRANSGENIC ANIMALS FOR TARGET VALIDATION;17
7.1.3;III. CONCLUSION;36
7.1.4;ACKNOWLEDGMENTS;36
7.1.5;RECOMMENDED RESOURCES;37
7.1.6;REFERENCES;37
7.2;Chapter 2 Target Validation in Chemogenomics;40
7.2.1;I. INTRODUCTION;40
7.2.2;II. REVERSE CHEMOGENOMICS: TARGET VALIDATION USING COMPOUNDS WITH KNOWN MOLECULAR TARGET (AND/OR MECHANISM OF ACTION);41
7.2.3;III. FORWARD CHEMOGENOMICS: TARGET IDENTIFICATION/VALIDATION USING COMPOUNDS WITH UNKNOWN MECHANISM OF ACTION;46
7.2.4;IV. CONCLUSION;50
7.2.5;REFERENCES;50
8;PART II TARGET VALIDATION FOR BIOPHARMACEUTICAL DRUG DISCOVERY;54
8.1;Chapter 3 Cetuximab (Erbitux®), An Anti-Epidermal Growth Factor Receptor Antibody for the Treatment of Metastatic Colorectal Cancer;56
8.1.1;I. INTRODUCTION;56
8.1.2;II. EPIDERMAL GROWTH FACTOR RECEPTOR AND ITS ROLE IN HUMAN CANCER;58
8.1.3;III. CETUXIMAB (ERBITUX®, IMC-C225);59
8.1.4;IV. CETUXIMAB IN CLINICAL STUDIES IN PATIENTS WITH mCRC;62
8.1.5;V. MECHANISMS OF ACTION OF CETUXIMAB;64
8.1.6;VI. CONCLUSIONS AND PERSPECTIVES;67
8.1.7;RECOMMENDED RESOURCES;72
8.1.8;REFERENCES;73
8.2;Chapter 4 Monoclonal Antibody to HER-2 in Breast Cancer;82
8.2.1;I. INTRODUCTION;82
8.2.2;II. MECHANISM OF ACTION OF TRASTUZUMAB;83
8.2.3;III. MOLECULAR MECHANISMS OF TRASTUZUMAB RESISTANCE;86
8.2.4;IV. ASSESSMENT OF HER-2 STATUS;87
8.2.5;V. CLINICAL TRIALS WITH TRASTUZUMAB;89
8.2.6;CONCLUSION;91
8.2.7;ACKNOWLEDGMENTS;91
8.2.8;USEFUL WEBSITES;92
8.2.9;REFERENCES;92
8.3;Chapter 5 Validation of TNF as a Drug Target in Inflammatory Bowel Disease;96
8.3.1;I. INTRODUCTION;97
8.3.2;II. TUMOR NECROSIS FACTOR;97
8.3.3;III. INFLAMMATORY BOWEL DISEASE;98
8.3.4;IV. PATHOPHYSIOLOGY OF IBD AND THE PUTATIVE ROLE OF TNF;100
8.3.5;V. CLINICAL EXPERIENCE WITH TNF-BLOCKING THERAPY IN IBD;104
8.3.6;CONCLUSION;112
8.3.7;ACKNOWLEDGMENTS;112
8.3.8;REFERENCES;112
8.4;Chapter 6 Anti–CCL-2/MCP-1: Directed Biologicals for Inflammatory and Malignant Diseases;116
8.4.1;I. INTRODUCTION;116
8.4.2;II. IN VITRO ASSAYS TO ESTABLISH THE PRO-INFLAMMATORY ACTIVITIES OF CCL-2;118
8.4.3;III. IN VIVO VALIDATION STUDIES;122
8.4.4;IV. SUMMARY;126
8.4.5;ACKNOWLEDGMENTS;127
8.4.6;REFERENCES;127
8.5;Chapter 7 Targeting IL-12p40 for Immune-Mediated Disease;134
8.5.1;I. INTRODUCTION;134
8.5.2;II. IN VITRO TARGET VALIDATION OF IL-12p40;135
8.5.3;III. IN VIVO PROOF-OF-CONCEPT FOR IL-12p40 INHIBITION;139
8.5.4;IV. CONCLUSION;143
8.5.5;RECOMMENDED RESOURCES;144
8.5.6;REFERENCES;144
8.6;Chapter 8 The GPIIb/IIIa Antagonist Abciximab for Acute Percutaneous Coronary Intervention;148
8.6.1;I. INTRODUCTION;148
8.6.2;II. RATIONALE FOR GPIIb/IIIa AS A TARGET IN CORONARY ARTERIAL DISEASE;149
8.6.3;III. GENERATION OF THE 7E3 MONOCLONAL ANTIBODY AGAINST GPIIb/IIIa;150
8.6.4;IV. IN VITRO STUDIES;150
8.6.5;V. ANIMAL STUDIES;154
8.6.6;VI. PLATELET PHARMACODYNAMIC PHENOMENA RECOGNIZED LATER;156
8.6.7;VII. CROSS REACTIVITY WITH OTHER INTEGRINS;158
8.6.8;VIII. INTEGRATION OF CLINICAL PHARMACOLOGY AND PRECLINICAL STUDIES;159
8.6.9;IX. CLINICAL STUDIES;160
8.6.10;X. CONCLUSION;162
8.6.11;RECOMMENDED RESOURCES;162
8.6.12;REFERENCES;162
9;PART III VALIDATING TARGETS OF SMALL MOLECULE APPROACHES;166
9.1;Chapter 9 Epidermal Growth Factor Receptor (EGFR) Inhibitor for Oncology: Discovery and Development of Erlotinib;168
9.1.1;I. INTRODUCTION;168
9.1.2;II. EPIDERMAL GROWTH FACTOR RECEPTOR AND LIGANDS;169
9.1.3;III. DISCOVERY OF AN EGFR INHIBITOR FOR DRUG DEVELOPMENT;177
9.1.4;IV. CONCLUSIONS;186
9.1.5;RECOMMENDED RESOURCES;186
9.1.6;REFERENCES;187
9.2;Chapter 10 Progress in Achieving Proof of Concept for p38 Kinase Inhibitors;192
9.2.1;I. INTRODUCTION;192
9.2.2;II. INHIBITORS;196
9.2.3;III. CLINICAL STATUS;207
9.2.4;IV. CONCLUSION;208
9.2.5;REFERENCES;209
9.3;Chapter 11 IKK-2/NF-kappa B–Dependent Transcription;212
9.3.1;I. INTRODUCTION;212
9.3.2;II. BIOLOGICAL ROLES OF NF-kappa B;213
9.3.3;III. ENZYMOLOGY;218
9.3.4;IV. IKK INHIBITORS;219
9.3.5;V. DISCUSSION/MECHANISM-BASED TOXICITY;226
9.3.6;VI. CONCLUSIONS AND OUTLOOK;228
9.3.7;RECOMMENDED OTHER READING;229
9.3.8;REFERENCES;230
9.4;Chapter 12 TNF Signaling Pathway Inhibitors for Inflammation-CCR2 Antagonists;236
9.4.1;I. INTRODUCTION;236
9.4.2;II. MACROPHAGES IN RHEUMATOID ARTHRITIS;238
9.4.3;III. MACROPHAGES IN MULTIPLE SCLEROSIS;239
9.4.4;IV. MACROPHAGES IN ATHEROSCLEROSIS;241
9.4.5;V. MACROPHAGES IN METABOLIC SYNDROME;242
9.4.6;VI. CCR2 ANTAGONISM AS A NEW APPROACH TO MODULATE INFLAMMATION;244
9.4.7;VII. CCR2 ANTAGONISM IN ARTHRITIS;244
9.4.8;VIII. CCR2 AND MULTIPLE SCLEROSIS;245
9.4.9;IX. CCR2 AND ATHEROSCLEROSIS;246
9.4.10;X. CCR2 AND DIABETES;248
9.4.11;XI. CONCLUDING REMARKS;248
9.4.12;RECOMMENDED RESOURCES;249
9.4.13;REFERENCES;250
9.5;Chapter 13 The Discovery of Eltrombopag, An Orally Bioavailable TpoR Agonist;254
9.5.1;I. THROMBOCYTOPENIA AND MEGAKARYOCYTOPOIESIS;255
9.5.2;II. THE DISCOVERY OF SMALL-MOLECULE TpoR AGONISTS AT GLAXOSMITHKLINE;257
9.5.3;CONCLUSIONS;265
9.5.4;ACKNOWLEDGMENTS;265
9.5.5;REFERENCES;266
9.6;Chapter 14 Orally Bioavailable Glycoprotein IIb/IIIa Antagonists: A Negative Case Study;268
9.6.1;I. INTRODUCTION;268
9.6.2;II. ROLE OF GP IIb/IIIa IN PLATELET BIOLOGY: CLUES FOR TARGET VALIDATION?;269
9.6.3;III. PHARMACOLOGY OF ORALLY BIOAVAILABLE GP IIb/IIIa ANTAGONISTS;272
9.6.4;IV. KEY RESULTS FROM PHASE III STUDIES;277
9.6.5;V. LACK OF EXPLANATION FOR EXCESS MORTALITY IN LARGE PHASE III TRIALS;278
9.6.6;CONCLUSIONS AND LESSONS LEARNED;280
9.6.7;REFERENCES;280
10;INDEX;282