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Target Validation in Drug Discovery
1st Edition - September 22, 2006
Editors: Brian W. Metcalf, Susan Dillon
Language: English
Hardback ISBN:9780123693938
9 7 8 - 0 - 1 2 - 3 6 9 3 9 3 - 8
eBook ISBN:9780080465975
9 7 8 - 0 - 0 8 - 0 4 6 5 9 7 - 5
This work presents a comprehensive contemporary framework for approaching target validation in drug discovery. It begins with a detailed description of new enabling technologies,…Read more
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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.
Professionals in biotechnology and pharmaceutical drug discovery and clinical development. Can also include students and academics in the related areas of study.
PREFACE
CONTRIBUTORS
I: Pharmaceutical biotechnology for target validation
Chapter 1: GENERATION OF TRANSGENIC ANIMALS
I INTRODUCTION
II GENERATION OF TRANSGENIC ANIMALS FOR TARGET VALIDATION
III CONCLUSION
ACKNOWLEDGMENTS
Chapter 2: TARGET VALIDATION IN CHEMOGENOMICS
I INTRODUCTION
II REVERSE CHEMOGENOMICS: TARGET VALIDATION USING COMPOUNDS WITH KNOWN MOLECULAR TARGET (AND/OR MECHANISM OF ACTION)
III FORWARD CHEMOGENOMICS: TARGET IDENTIFICATION/VALIDATION USING COMPOUNDS WITH UNKNOWN MECHANISM OF ACTION
IV CONCLUSION
II: Target validation for biopharmaceutical drug discovery
Chapter 3: CETUXIMAB (ERBITUX®), AN ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODY FOR THE TREATMENT OF METASTATIC COLORECTAL CANCER
I INTRODUCTION
II EPIDERMAL GROWTH FACTOR RECEPTOR AND ITS ROLE IN HUMAN CANCER
III CETUXIMAB (ERBITUX®, IMC-C225)
IV CETUXIMAB IN CLINICAL STUDIES IN PATIENTS WITH mCRC
V MECHANISMS OF ACTION OF CETUXIMAB
VI CONCLUSIONS AND PERSPECTIVES
Chapter 4: MONOCLONAL ANTIBODY TO HER-2 IN BREAST CANCER
I INTRODUCTION
II MECHANISM OF ACTION OF TRASTUZUMAB
III MOLECULAR MECHANISMS OF TRASTUZUMAB RESISTANCE
IV ASSESSMENT OF HER-2 STATUS
V CLINICAL TRIALS WITH TRASTUZUMAB
CONCLUSION
ACKNOWLEDGMENTS
USEFUL WEBSITES
Chapter 5: VALIDATION OF TNF AS A DRUG TARGET IN INFLAMMATORY BOWEL DISEASE
I INTRODUCTION
II TUMOR NECROSIS FACTOR
III INFLAMMATORY BOWEL DISEASE
IV PATHOPHYSIOLOGY OF IBD AND THE PUTATIVE ROLE OF TNF
V CLINICAL EXPERIENCE WITH TNF-BLOCKING THERAPY IN IBD
CONCLUSION
ACKNOWLEDGMENTS
Chapter 6: ANTI-CCL-2/MCP-1: DIRECTED BIOLOGICALS FOR INFLAMMATORY AND MALIGNANT DISEASES
I INTRODUCTION
II IN VITRO ASSAYS TO ESTABLISH THE PRO-INFLAMMATORY ACTIVITIES OF CCL-2
III IN VIVO VALIDATION STUDIES
IV SUMMARY
ACKNOWLEDGMENTS
Chapter 7: TARGETING IL-12P40 FOR IMMUNE-MEDIATED DISEASE
I INTRODUCTION
II IN VITRO TARGET VALIDATION OF IL-I2p40
III ÌN VÌVO PROOF-OF-CONCEPT FOR IL-I2p40 INHIBITION
IV CONCLUSION
Chapter 8: THE GPIIB/IIIA ANTAGONIST ABCIXIMAB FOR ACUTE PERCUTANEOUS CORONARY INTERVENTION
I INTRODUCTION
II RATIONALE FOR GPIIb/IIIa AS A TARGET IN CORONARY ARTERIAL DISEASE
III GENERATION OF THE 7E3 MONOCLONAL ANTIBODY AGAINST GPIIb/IIIa
IV IN VITRO STUDIES
V ANIMAL STUDIES
VI PLATELET PHARMACODYNAMIC PHENOMENA RECOGNIZED LATER
VII CROSS REACTIVITY WITH OTHER INTEGRINS
VIII INTEGRATION OF CLINICAL PHARMACOLOGY AND PRECLINICAL STUDIES
IX CLINICAL STUDIES
X CONCLUSION
III: Validating targets of small molecule approaches
Chapter 9: EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) INHIBITOR FOR ONCOLOGY: DISCOVERY AND DEVELOPMENT OF ERLOTINIB
I INTRODUCTION
II EPIDERMAL GROWTH FACTOR RECEPTOR AND LIGANDS
III DISCOVERY OF AN EGFR INHIBITOR FOR DRUG DEVELOPMENT
IV CONCLUSIONS
Chapter 10: PROGRESS IN ACHIEVING PROOF OF CONCEPT FOR p38 KINASE INHIBITORS
I INTRODUCTION
II INHIBITORS
III CLINICAL STATUS
IV CONCLUSION
Chapter 11: IKK-2/NF-κB-DEPENDENT TRANSCRIPTION
I INTRODUCTION
II BIOLOGICAL ROLES OF NF-κB
III ENZYMOLOGY
IV IKK INHIBITORS
V DISCUSSION/MECHANISM-BASED TOXICITY
VI CONCLUSIONS AND OUTLOOK
Chapter 12: TNF SIGNALING PATHWAY INHIBITORS FOR INFLAMMATION-CCR2 ANTAGONISTS
I INTRODUCTION
II MACROPHAGES IN RHEUMATOID ARTHRITIS
III MACROPHAGES IN MULTIPLE SCLEROSIS
IV MACROPHAGES IN ATHEROSCLEROSIS
V MACROPHAGES IN METABOLIC SYNDROME
VI CCR2 ANTAGONISM AS A NEW APPROACH TO MODULATE INFLAMMATION
VII CCR2 ANTAGONISM IN ARTHRITIS
VIII CCR2 AND MULTIPLE SCLEROSIS
IX CCR2 AND ATHEROSCLEROSIS
X CCR2 AND DIABETES
XI CONCLUDING REMARKS
Chapter 13: THE DISCOVERY OF ELTROMBOPAG, AN ORALLY BIOAVAILABLE TpoR AGONIST
I THROMBOCYTOPENIA AND MEGAKARYOCYTOPOIESIS
II THE DISCOVERY OF SMALL-MOLECULE TpoR AGONISTS AT GLAXOSMITHKLINE
CONCLUSIONS
ACKNOWLEDGMENTS
Chapter 14: ORALLY BIOAVAILABLE GLYCOPROTEIN IIB/IIIA ANTAGONISTS: A NEGATIVE CASE STUDY
I INTRODUCTION
II ROLE OF GP IIb/IIIa IN PLATELET BIOLOGY: CLUES FOR TARGET VALIDATION?
III PHARMACOLOGY OF ORALLY BIOAVAILABLE GP IIb/IIIa ANTAGONISTS
IV KEY RESULTS FROM PHASE III STUDIES
V LACK OF EXPLANATION FOR EXCESS MORTALITY IN LARGE PHASE III TRIALS
CONCLUSIONS AND LESSONS LEARNED
INDEX
No. of pages: 296
Language: English
Edition: 1
Published: September 22, 2006
Imprint: Academic Press
Hardback ISBN: 9780123693938
eBook ISBN: 9780080465975
BM
Brian W. Metcalf
Affiliations and expertise
Chief Drug Discovery Officer, Incyte Corporation, Moraga, CA, U.S.A.
SD
Susan Dillon
Affiliations and expertise
Senior Vice President, Discovery Research Centocor, Johnson & Johnson, Malvern, PA, U.S.A.
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