Target Validation in Drug Discovery

1st Edition - September 22, 2006
Editors: Brian W. Metcalf, Susan Dillon
Language: English
Hardback ISBN:
9 7 8 - 0 - 1 2 - 3 6 9 3 9 3 - 8
eBook ISBN:
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.

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

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

Health

Target Validation in Drug Discovery

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Brian W. Metcalf

Susan Dillon

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