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The Future of Personalized Medicine: The Impact of Proteomics on Drug Discovery And Clinical Trial Design
Business Insights, Oct 2004
The Future of Personalized Medicine: The Impact of
Proteomics on Drug Discovery and Clinical Trial Design
Executive summary 10
Introduction to proteomics 10
Proteomic technologies 11
Proteomic applications in drug discovery 13
Proteomic applications in clinical trial design and personalized medicine 14
Pharma and proteomic company alliances 15
Chapter 1 Introduction to proteomics 17
Summary 17
Introduction 18
The human genome versus the proteome 20
Identification of human genome 20
Applications to proteomics 21
The relationship between the proteome and the genome 23
The genome 23
Proteins 24
From genes to proteins 27
Proteomics 29
Conclusions 30
Chapter 2 Proteomic technologies 33
Summary 33
Laboratory methods used in proteomics 34
Separation techniques 34
Identification techniques 34
Interactions techniques 34
Separation techniques 38
2-dimensional polyacrylamide gel electrophoresis (2-D PAGE) 38
Liquid chromatography (LC) 38
Protein arrays 39
Identification techniques 40
Mass spectrometry 40
Protein-protein interaction techniques 42
Automation 43
Pre-fractionation 43
Separation 44
Identification 45
Complete proteomics solutions 46
The future of automation in proteomics 46
Conclusions 48
Bioinformatics and databases 49
Data analysis 50
Databases 50
Laboratory information management systems (LIMS) 52
Conclusions 53
Overall conclusions 53
Chapter 3 Proteomic applications in drug
discovery 57
Summary 57
Introduction 58
Optimizing the R&D process 60
Early selection of efficacious and non-toxic drug targets 65
Toxicoproteomics 67
Pharmacoproteomics 68
Conclusions 69
Accelerating the discovery of new targets for therapeutic candidates 70
Therapeutic proteins 70
Protein targets 74
Mining the proteome is an alternative approach for drug discovery 74
Conclusions 75
Chapter 4 Proteomic applications in clinical
trial design and personalized
medicine 77
Summary 77
Development of new biomarkers 78
Biomarkers as clinical endpoints 80
Responders and non-responders 80
Patients with adverse reactions 82
Patients in different stages of a disease, or other subsets of patients 82
Monitor clinical responses in new and comparator drugs - allowing potential
strategic alliances 84
Patients with disease resistance 85
Niche markets 86
Conclusions 86
Application of biomarkers by therapy area 87
Oncoproteomics 88
Application in the diagnosis of ovarian cancer 88
Application in the diagnosis of prostate cancer 89
Application in the diagnosis of breast cancer 89
Application in the diagnosis of esophageal cancer 90
Neuroproteomics 90
Application in the diagnosis of Alzheimer’s diseases 90
Application in the diagnosis of amyotrophic lateral sclerosis (ALS) 91
Cardioproteomics 91
Cardiovascular markers 91
Respiratory markers 92
Application in organ transplantation 92
Post-marketing applications of biomarkers 93
Conclusions 94
Conclusions 95
Conclusions 95
Chapter 5 Pharmaceutical and proteomic
company alliances 99
Summary 99
Introduction 100
Recent collaborations and alliances of pharma and proteomic based
companies 102
Abbott 102
Altana 102
AstraZeneca 102
Aventis 103
Bayer 104
Bristol-Myers Squibb 104
Boehringer Ingelheim 105
Daiichi 106
Eli Lilly 106
Fujisawa 107
GlaxoSmithKline 107
Johnson & Johnson 107
Lundbeck 107
Merck & Co. 108
Merck KGaA 108
Novartis 108
Pfizer 109
Proteome Sciences 110
Procter & Gamble 110
Roche 110
Schering AG 111
Sumitomo Chemical 111
Takeda 113
UCB 114
Wyeth 114
Conclusions 114
Chapter 6 Appendix 117
2-dimensional polyacrylamide gel electrophoresis (2-D PAGE) 117
Summary 119
Liquid chromatography (LC) 120
Gel filtration chromatography 121
Ion exchange chromatography 121
Affinity chromatography 121
Partitioning chromatography 122
LC summary 122
High performance liquid chromatography 122
Protein arrays 123
Expression arrays 124
Functional arrays 126
Reverse arrays 126
Protein array summary 127
Mass spectrometry (MS) 128
Electro-spray ionization 130
Laser desorption/ionization 132
MALDI 132
SELDI 133
Protein-protein interactions 135
Fluorescence resonance energy transfer 137
Bioinformatics databases 138
Summary 138
Sequence databases and alignment tools 139
Domain and 3-dimensional structure databases 140
Databases of biochemical pathways 142
‘Techniques’ databases 143
The human proteome organization 144
Index 145
References 147
Website references 154
List of Figures
Figure 1.1: Nearly 500 proteins identified through proteomics have known functions in disease21
Figure 1.2: The basic structure of the (unwound) DNA helix 23
Figure 1.3: The general structure of an amino acid and peptide bond 25
Figure 1.4: The active site of the bacterial serine protease subtilisin 26
Figure 1.5: The process of protein synthesis 27
Figure 2.6: Techniques used in proteomics 36
Figure 2.7: The role and scope of bioinformatics in proteomics research 49
Figure 3.8: Only 30% of drugs produce revenues that exceed the average R&D cost 60
Figure 3.9: Industry average attrition curves, 2004 61
Figure 3.10: US pharmaceutical industry R&D expenditure and NCEs approvals, 1995-2003 62
Figure 3.11: Strategies for analysis of toxicoproteomic data 67
Figure 3.12: The impact of protein probes on drug discovery 73
Figure 4.13: Three stages of diagnostic development 79
Figure 4.14: The predicted individual response to any one drug 81
Figure 6.15: Example of a 2-D PAGE gel 118
Figure 6.16: Representation of liquid chromatography 120
Figure 6.17: Typical high performance liquid chromatography set-up 123
Figure 6.18: Representation of a ‘sandwich’ – type expression array 125
Figure 6.19: A typical ESI instrument set up 131
Figure 6.20: Simplified diagram of MALDI apparatus 133
Figure 6.21: Representation of the yeast two hybrid system 136
Figure 6.22: Schematic representation of FRET for investigating protein-protein interactions 137
Figure 6.23: Representation of FRET for investigating protein-protein interactions 142
Figure 6.24: Example of a pathway diagram from KEGG 143
List of Tables
Table 1.1: The single- and three-letter amino acid codes 24
Table 1.2: The codons and the amino acids that they specify 28
Table 2.3: Summary of key proteomics technologies 37
Table 2.4: A selection of protein array manufacturers* 40
Table 2.5: Automation of proteomic platforms 47
Table 2.6: Summary of proteomics databases* 51
Table 3.7: Constant dollar reduction in total cost per new drug, 2002 62
Table 3.8: R&D spend on drug development, 2002 65
Table 3.9: New biologics 70
Table 3.10: Recombinant proteins 71
Table 3.11: Protein drug targets 72
Table 3.12: New proteomic targets 74
Table 4.13: Proteomic biomarkers 79
Table 4.14: Correlation of survival with HER-2 over-expression 83
Table 5.15: Colloborations implementing proteomics technologies 101
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