Abstract
The shift from traditional to genomics-and proteomics-based drug discovery has fundamentally changed the way researchers view the subject of targets. After decades of focusing on a few hundred relatively well-characterized therapeutic targets, drug developers are now finding that the genomics revolution has presented them with the opposite dilemma: thousands of prospective targets about which little is known. Powering Discovery through Target Evaluation: Moving beyond the Validation Paradigm comprehensively evaluates current efforts to solve the target validation problem.
With steadily growing drug development costs, depleted pipelines, and few blockbusters on the horizon, the ability to quickly identify the most biologically promising of these targets will be the single-largest differentiator between the winners and losers within the research-based pharmaceutical industry over the next decade. Target validation thus becomes the central issue in the success or failure of pharmaceutical R&D. Researchers must find the means to choose the best drug targets early in the process to reduce costly attrition rates and allow for more efficient drug discovery and development.
Powering Discovery through Target Evaluation: Moving beyond the Validation Paradigm offers unique and insightful analysis of current efforts to sift through the post-genomic data deluge, prioritize targets, and optimize resources to develop the most promising leads. This report:
- Reviews the key issues with the current target validation paradigm.
- Evaluates the tools and business strategies of select companies competing in this arena.
- Analyzes efforts to use proteomic techniques for target validation.
- Addresses applications of RNAi technology to target validation and pathway mapping.
- Examines the issue of multiple molecular "causes" of disease by developing therapies (including single drugs and combination therapies) that address more than one molecular target.
- Discusses whole pathway approaches to drug discovery--a crucial step toward understanding the function of poorly characterized targets. Pathway analysis may also be important in patient stratification.
- Evaluates the current status of translational medicine as a strategy for improving the productivity of drug development.
Table of Contents
Chapter 1. Introduction
- 1.1. What Is a Drug Target?
- 1.2. The Target Validation Problem
- 1.3. Critiques of the Target Validation Paradigm
Chapter 2. Target Evaluation Technologies
- 2.1. Target Identification Technologies
- DNA Microarrays
- Expression Proteomics
- Bioinformatics and Data Mining
- Human Genetics
- 2.2. Target Characterization Technologies
- 2.3. Target Validation Technologies
- RNA Interference (RNAi)
- Model Organisms
- 2.4. Exelixis and Lexicon Genetics: From Model Organism Technology Companies to Drug Discovery
and Development Companies
- Exelixis
- Lexicon Genetics
Chapter 3. Whole-Pathway Approaches to Drug Discovery
- 3.1. Bionaut
- 3.2. BioImage
- 3.3 Avalon Pharmaceuticals
Chapter 4. Approaches to Developing Therapies That Address Multiple Molecular Targets
- 4.1. CombinatoRx
- 4.2. Cyclacel
- 4.3. Companies Developing Kinase Inhibitors That Address Multiple Targets
Chapter 5. Targets and "Druggability" for Small- and Large Molecule Drugs
Chapter 6. Biology-Driven and Technology-Driven Target Evaluation and Drug Discovery/Development Strategies
- 6.1. Technology-Driven Strategies
- 6.2. Biology-Driven Strategies
- 6.3. A Comparison of Biology- and Technology-Driven Strategies
Chapter 7. Understanding Complex Diseases with High Unmet Need
- 7.1. Genetics-Based Programs in Complex Diseases
- 7.2. BiDil, an Example of Dealing with a Complex, Heterogeneous Disease with Incomplete Knowledge
- 7.3. Biomarkers, Complex Diseases, and Patient Stratification
- 7.4. Biomarkers and Translational Mecidince
- 7.5. Animal Models in Understanding Complex Diseases and Developing Therapeutic Strategies
Chapter 8. Targets and Business Issues in Early-Stage Partnerships
- 8.1. Pharma and Biotech Approaches to Early-Stage Agreements
- Novartis
- Merck
- GlaxoSmithKline
- Genentech
Appendix
- Selected Company Profiles
- AstraZeneca Pharmaceuticals
- Cellomics
- CombinatoRx
- Exelixis
- Genentech
- Novartis Institutes for BioMedical Research (NIBR)
- Pfizer
- Wyeth Pharmaceuticals
References
Glossary
Index
