THE EMERGING DRUG TARGETS OUTLOOK:
An Analysis Of Novel Molecular Targets
To Develop Innovative New Therapeutics
TABLE OF CONTENTS
EXECUTIVE SUMMARY
CHAPTER 1 THE DRUG TARGET LANDSCAPE
1.1 Description and comparison of drug targets
1.1.1 Introduction
1.1.2 Cytokines and chemokines
1.1.3 G protein-coupled receptors
1.1.4 Glycosidases/glycosyltransferases
1.1.5 Ion channels
1.1.6 Nuclear receptors
1.1.7 Phosphodiesterases
1.1.8 Proteases
1.1.9 Protein kinases
1.1.10 Protein phosphatases
1.1.11 Nucleic acids
1.1.12 Transporters
1.2 Targeting cell signaling
1.2.1 Focus on G protein coupled receptors
1.2.2 Focus on protein kinases
1.2.3 Focus on nuclear receptors
CHAPTER 2 DRUG TARGET SELECTION
2.1 Marketed drug classes
2.1.1 Number of marketed drugs
2.1.2 Sales of marketed drugs
2.2 Defining the most promising drug targets
2.2.1 Potential number of targets
2.2.2 Sales potential
2.2.3 Drug discovery spend
2.2.4 Pipeline activity
2.2.5 Failure rates in clinical trials
2.2.6 Company focus
2.2.7 Target class by therapy area
2.2.8 Growing therapy areas
2.2.9 Conclusions
CHAPTER 3 GPCRS
3.1 Overview
3.2 Description and segmentation of GPCRs
3.2.1 Description
3.2.2 Segmentation
3.2.3 Overview of class 1 receptors
3.2.3.1 Serotonin
3.2.3.2 Dopamine
3.2.3.3 Adrenergic
3.2.3.4 Histamine
3.2.3.5 Muscarinic
3.2.3.6 Nucleotide
3.2.3.7 Cannabinoid
3.2.3.8 Chemokine
3.2.3.9 Opioid
3.2.4 Overview of class 2 receptors
3.2.5 Overview of class 3 receptors
3.3 Intellectual property landscape
3.4 Marketed drugs/pipeline drugs
3.4.1 Marketed drugs
3.4.2 Pipeline drugs
3.4.2.1 Targeting class 1 receptors
3.4.2.2 Targeting class 2 and 3 receptors
3.4.2.3 New directions in GPCR drug development
3.5 Companies involved in class/key industry players
3.6 Projected impact across therapy areas
3.7 Case study
CHAPTER 4 KINASES
4.1 Overview
4.2 Description and segmentation of protein kinases
4.3 Intellectual property landscape
4.4 Marketed drugs/pipeline drugs
4.4.1 Marketed drugs
4.4.2 Pipeline drugs
4.4.2.1 New directions in kinase drug development
4.5 Companies involved in class/key industry players
4.6 Projected impact across therapy areas
4.7 Case study
CHAPTER 5 NUCLEAR RECEPTORS
5.1 Overview
5.2 Description and segmentation of nuclear receptors
5.3 Intellectual property landscape
5.4 Marketed drugs/pipeline drugs
5.4.1 Marketed drugs
5.4.2 Pipeline drugs
5.4.2.1 New directions in drug development
5.5 Companies involved in class/key industry players
5.6 Projected impact across therapy areas
5.7 Case study
CHAPTER 6 IMPLICATIONS FOR DRUG DISCOVERY
6.1 The trend towards target-led drug discovery
6.1.1 Redefining diseases at the molecular level
6.1.2 Expanding the target universe
6.1.3 Enabling in silico drug discovery
6.2 Comparison of three promising target categories
6.2.1 Factors impacting future prospects
CHAPTER 7 APPENDIX
Tables of US top 100 drugs
Research methodology
Glossary
Index
LIST OF FIGURES
Figure 1.1: Classes of GPCR genes with known ligands
Figure 2.2: Sales per drug target class of the top 100 drugs
in the US ($bn), 2003-04
Figure 3.3: Schematic drawing of a typical GPCR showing all seven
transmembrane domains
Figure 3.4: Virtual selection for drug screening
Figure 4.5: Kinase inhibitor Gleevec complexed with spleen
tyrosine kinase
Figure 5.6: Ligand binding fragment of the human nuclear
oestrogen receptor complexed with the oestrogen
antagonist raloxifene.
Figure 6.7: Adjusted US patent shares by target class, 2000-2004
Figure 6.8: Published US patents by target class, 2000-2004
Figure 6.9: Therapeutic focus of published US patents by target
class, 2000-2004
LIST OF TABLES
Table 2.1: Drug target classes of the top 100 drugs
in the US, 2003-04
Table 2.2: Current and forecast global sales by
therapy area, 2004 & 2009
Table 2.3: Target gene numbers
Table 2.4: Target group sales forecasts, 2005-09
Table 2.5: Estimated preclinical R&D spend by target class, 2004
Table 2.6: US patents mentioning each target
Table 2.7: Estimated drugs in development by target, May 2004
Table 2.8: Top 5 US patent assignees by target category, 2000-04
Table 2.9: Target classes of the US top 100 drugs by
therapeutic area and company, 2004
Table 2.10: Growth rates of therapy areas, 2004
Table 3.11: GPCR patent analysis, 2000-04
Table 3.12: Patent filing and publication years for GPCRs
Table 3.13: Top 20 GPCR-targeting drugs by US sales, 2004
Table 3.14: GPCR patent assignees, 2000-04
Table 3.15: GPCR patent citations, 2000-04
Table 4.16: Classification of protein kinases
Table 4.17: Kinase patent analysis, 2000-04
Table 4.18: Patent filing and publication years for protein kinases
Table 4.19: Protein kinase patent assignees, 2000-04
Table 4.20: Top 20 protein kinase patent citations, 2000-04
Table 5.21: Classification of nuclear receptors
Table 5.22: Nuclear receptor patent analysis, 2000-04
Table 5.23: Patent filing and publication years for nuclear receptors
Table 5.24: Top 10 nuclear receptor-targeting drugs by US sales, 2004
Table 5.25: Nuclear receptor patent assignees, 2000-04
Table 5.26: Nuclear receptor patent citations, 2000-04
Table 7.27: US top 100 drugs ranked by sales, 2003-04
Table 7.28: US top 100 drugs by sales growth, 2003-04
Table 7.29: US top 100 drugs by target class and sales, 2003-04
Table 7.30: US top 100 drugs by therapeutic area and target, 2003-04
EXECUTIVE SUMMARY
Chapter 1 The drug target landscape
- In this chapter the major drug target classes are introduced,
with a focus on druggable protein superfamilies.
- The following drug target classes are reviewed: G protein
coupled receptors (GPCRs); cytokines and chemokines;
glycoenzymes; ion channels; nuclear receptors;
phosphodiesterases; proteases; protein kinases; protein
phosphatases; nucleic acids; and transporters.
- Aberrant signal transduction plays a key part in the
pathology of many serious diseases including cancer,
inflammatory, cardiovascular, metabolic, and neuropsychiatric
diseases.
- Proteins involved in signal transduction pathways therefore
represent important drug targets.
- Three prominent superfamilies of proteins involved in signal
transduction are: GPCRs, protein kinases, and nuclear
receptors.
- The roles of GPCRs, protein kinases and nuclear receptors in
signal transduction pathways are discussed.
Chapter 2 Drug target selection
- A target-oriented view of the pharmaceuticals market is
presented as a basis for investigations aimed at determining
which target subclasses are most likely to progress beyond
the R&D stage.
- Successful marketed drug classes are analysed as well as
product pipeline activity in each class.
- Appropriately chosen metrics can provide an objective
approach to predicting target quality.
- Analysis of the 100 best-selling drugs on the US market
reveals the most lucrative and the fastest-growing target
classes and therapy sectors, as well as the identity of
companies in each target class space.
- In further evaluating drug target classes, use has been made
of a range of metrics, including: potential number of
targets; sales potential; preclinical R&D spend; pipeline
activity; failure rates in clinical trials.
- Analysis of US patenting activity reveals the leading
companies in each target class.
Chapter 3 GPCRs
- GPCRs are instrumental in the transmission of signals from
the extracellular environment to the interior of the cell.
- GPCRs are a highly successful drug target class and many
targets are now well-established.
- Genomic approaches have produced new targets to explore.
- Crystallization of GPCRs has proven challenging, as has
research on ligands to orphan receptors.
- The three main classes of GPCRs are examined.
- Marketed drugs, including the top 20 best-selling drugs, and
pipeline products, of which there is an abundance, are
discussed.
- Examination of patenting trends over the last 5 years reveals
the nature of claims made and the identity of the most
prolific and the most influential assignees.
- A case study is presented which describes Argenta Discovery's
efforts to develop and apply virtual screening methodologies
to hit generation in GPCR-based drug discovery.
Chapter 4 Protein kinases
- Protein kinases play a central role in diverse signal
transduction pathways.
- The development of small molecule inhibitors of kinase enzyme
activity progressed slowly prior to 1998.
- In recent years the FDA has approved three kinase-targeting
small molecule and two monoclonal antibody drugs.
- Around 240 drugs targeting protein kinases are in
development.
- Genomic approaches have yielded new targets to explore.
- The characteristic features of serine/threonine protein
kinase and protein tyrosine kinase targets are discussed.
- Examination of patenting trends over the last 5 years reveals
nature of claims made and the identity of the most prolific
and the most influential assignees.
- A case study is presented which describes Biogen Idec's
discovery of a potent inhibitor of TGF-beta receptor 1 kinase
using shape-based virtual screening.
Chapter 5 Nuclear receptors
- Nuclear receptors function as transcriptional regulators of
gene expression.
- Nuclear receptors are natural targets for small molecule drug
discovery because they have evolved to interact with a wide
range of small molecules.
- This class has produced many commercially viable
pharmaceuticals.
- Although analysis of the complete human genome failed to
identify new genes, the nuclear receptors as drug targets are
growing in importance as the role of many orphan receptors is
revealed.
- The characteristics of nuclear receptors belonging to the six
major families are reviewed.
- Marketed drugs, including the top 10 best-selling drugs and
drugs in development are discussed.
- Examination of patenting trends over the last 5 years reveals
the nature of claims made and the identity of the most
prolific and the most influential assignees.
- A case study is presented which describes Inpharmatica's
discovery of 16 novel nuclear receptor targets using its
informatics-driven chemogenomics platform.
Chapter 6 Implications for drug discovery
- The factors assisting the trend towards target-led drug
discovery are examined.
- Target-led drug discovery will benefit from diseases being
redefined at the molecular level, an expanded target
universe, and advances in in silico drug discovery.
- Analysis of 5-year (2000-04) patenting activity centered
oneach of the three promising drug target classes examined in
Chapters 3-5 (GPCRs, protein kinases, and nuclear receptors)
was undertaken.
- Although productivity in drug research and development in
general continues to fall, the IP landscape examined here
reveals a recent wave of patents which are are likely to give
rise to new products in the future.
- Comparison of the therapeutic focus and volume of patents
relating to the three drug target classes offers further
clues as to when and how they may impact drug discovery.
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