激脢：最新新药研发策略及多重目标

Abstract

The kinase-targeted drug market is forecast to reach $58.6 billion in 2010.

D&MD's Kinases: Advanced Strategies for Drug Discovery market analysis report comprehensively reviews protein kinases and assesses their importance as drug targets. Approaches to kinase drug discovery are evolving. Small molecule inhibitors now encompass rationally-designed single-target inhibitors and multi-target inhibitors developed with the aid of new screening and profiling assays. Innovative biopharmaceuticals are making inroads into the market. The range of indications for kinase-targeted drugs is expanding.

During the last five years, eight anticancer kinase inhibitors received FDA approval, including multi-kinase inhibitors, the first of which was approved by the FDA in December 2005. The launched drugs are discussed in this report, as are similar agents that are following in their track. At the same time, recent discoveries of activating and resistance kinase mutations have been driving the development of molecularly targeted anticancer therapies and we review progress in this area. An on-line survey conducted specially for this report shows that kinases (alongside GPCRs), are currently regarded as commercially the most promising targets available to the drug industry. The facts and analysis provided by this report help companies prepare themselves to exploit these targets.

Chapter 1: E xecutive Summary

During the last five years, eight anticancer kinase inhibitors received FDA approval, increasing recognition of kinases as an important class of drug targets. In order to comprehensively assess the scientific, clinical, and commercial progress and prospects in this field, the following surveys were carried out exclusively for this report: a search of Pharmaprojects, the leading database tracking pharmaceutical R&D worldwide; a survey of the last six years of kinase-related patenting at the US PTO; and an on-line survey of pharmaceutical industry and academic personnel. We forecast that the kinase-targeted drug market will grow from $12.7 billion in 2005 to $58.6 billion in 2010. Cancer (mainly solid tumors) will remain the dominant application throughout the forecast period.

Reversible protein phosphorylation, catalyzed by kinases, is a ubiquitous mechanism for the control of signal transduction networks that regulate many vital biological processes. Cancer and other proliferation-related disorders are associated with stimulation of intra-cellular signaling, and since kinases (most of the time) positively relay signaling events; their inhibition offers a powerful way to block aberrant signal transduction cascades. The focus throughout this report is on inhibitors of protein kinases, although, where appropriate, protein kinase stimulators are also discussed, as are modulators of lipid and sugar kinases. The search of the Pharmaprojects database generated 803 drug profiles representing 243 unique companies, 184 unique targets, and 68 unique indications/drug types. A subsequent search of the Entrez Gene database for human genes with kinase activity led us to conclude that (according to Pharmaprojects) 145 kinase-related genes are currently drug targets, while 627 kinase-related genes remain unexplored as drug targets.

Examination of the Pharmaprojects dataset revealed that the kinase drug market is at an early stage; overall 80% of drugs are still in preclinical development. By far the largest indication for kinase-targeted drugs, almost 41% of the total, is cancer. Of the top five kinase drug targets, only one is not primarily a cancer target. Other important indications for kinase-targeted drugs include inflammation, arthritis, diabetes, and cardiovascular disease. Of the top ten companies most active in this area, only Pfizer, Novartis, AstraZeneca, and GlaxoSmithKline have launched products.

Currently, the emphasis is on small molecule approaches to kinase inhibition. The majority of the respondents to our on-line survey felt that small molecule inhibitors were preferable to monoclonal antibodies and that multi-target kinase inhibitors were more likely to prove commercially successful than single-target inhibitors. Now that many kinases have been sequenced and their structures have been determined, more efficient approaches to small molecule kinase inhibitor discovery are urgently needed. We discuss recent advances in this area,

Buy this report and receive:

• Results from a survey of more than 800 kinase drugs and their targets to give the reader an appreciation of the kinase drug landscape
• Current market size and forecasts to 2010 to assist the reader with formulating business plans in the kinase drug area
• Analysis on the leading indications for kinase drugs and highlights in areas of unmet needs to enable the reader to formulate a strategy for business development
• Profiles of kinase-related patenting at the US PTO to help the reader understand the area's evolving IP landscape, identify trends, improve strategic approach and discover potential collaborative partners
• Comprehensive analysis of kinase drug targets through a gene family-based approach to allow the reader to assess the drug development potential of kinases belonging to particular families

Receive answers to crucial questions in this area such as:

• Which kinase targets are being pursued by drug developers?
• Which kinase targets have attracted the greatest amount of interest from drug developers?
• What is the nature of commercial activity surrounding each major kinase target?
• Which are the most important therapeutic indications for kinase drugs?
• What are the areas of unmet need that new kinase drugs could address?
• Which companies are the most prolific developers of kinase drugs and what drugs are in their portfolios?
• Who are the most prolific assignees and which are the most frequently cited kinase patents?

Recent approvals of several first-in-class kinase inhibitors have resulted in increased recognition of kinases as an important class of drug targets. The kinase market is still at an early stage, but many trends are already evident and these are analyzed in this report. Already 145 kinase-related genes are being targeted in kinase drug development, which nonetheless leaves a large number (estimated 627) of potential targets unexplored. This report guides readers in assessing or reassesing their strategies with respect to this target class.

In order to comprehensively assess recent progress and prospects in the kinase field, several surveys were carried out exclusively for this report, involving searches of the Pharmaprojects database and the U.S. Patent and Trademark Office database, and questioning of respondents from the pharmaceutical industry. The information from the various surveys was utilized in the analysis of individual kinase targets and families to which they belong.

Table of Contents

Chapter 1: Executive Summary

Chapter 2: Why Target Kinases?

• Introduction
• Overview of Human Protein Kinases
  • Classification Schemes
• Kinases in Signal Transduction Pathways
  • MAP Kinase Pathways
    • MAPK (ERK) Pathway
    • JNK/SAPK Pathway
    • p38 MAPK Pathway
  • PI3K/Akt Signaling
  • Jak/STAT Signaling
    • Jak/STAT3 Signaling in Cancer
  • Insulin Receptor Signaling
  • NFk-B Pathway
    • TNF Signaling in Cancer
  • Immune Cell Signaling
    • T-Cell Receptor Signaling
    • B-Cell Receptor Complexes
  • Signaling in Vascular Morphogenesis
    • VEGF Receptor Signaling
  • EGF Receptor Signaling
  • Cyclic Nucleotide Metabolism
  • Cell Cycle Checkpoint Controls
• Categories of Kinase-targeted Drugs
  • Small Molecules
  • Biopharmaceuticals
• Survey of Kinase Inhibitors Under Development
  • Developing Companies
  • Indications
  • Targets
  • Categories (origin of material)

Chapter 3: Focus on Small Molecule Kinase Inhibitors

• Introduction
  • Mechanisms of Kinase Inhibition
• The Kinase Drug Discovery Process
  • Improving Target Validation
    • Use of RNAi and Aptamers
  • Improving HTS Processes
  • Improving Structure-based Drug Design
  • Monitoring Kinase Activity
    • Primary Screens
    • Secondary Screens
    • Cell-based Assays
• Identifying Substrates of Novel Kinases
  • In vitro and In vivo Assays
  • Use of Peptide Libraries
  • Use of Protein Microarrays

Chapter 4: Kinase Targets in Cancer

• Introduction
• Overview of Cancer
  • Established Therapies
  • Molecular Targeted Therapies
• Kinases in Cancer
  • Kinase Profiling of Individual Tumors
• Inhibiting Multiple Cancer-related Kinases
  • Multi-Target Kinase
• Protein Kinases as Drug Targets
• TK Group
  • Abl Family
    • Gleevec (imatinib)
    • Sprycel (dasatinib)
    • Nilotinib
  • EGFR Family
    • Herceptin (trastuzumab)
    • Erbitux (cetuximab)
    • Iressa (gefitinib)
    • Tarceva (erlotinib)
    • Lapatinib
  • Eph Family
  • FGFR Family
  • VEGFR Family
  • PDGFR Family
  • Src Family
  • Ret Family
  • Trk Family
• TKL Group
  • RAF Family
• AGC Group
  • AKT Family
  • PKC Family
• CMGC Group
  • CDK Family
  • MAPK Family
• STE Group
• "Other" Group
  • Aurora Family
• Atypical Group
• Dual Specificity Lipid/Protein Kinases

Chapter 5: Protein Kinase Targets in Other Diseases

• Introduction
• Inflammation and Tissue Injury
  • Background
    • Current Treatments
  • Kinase Targets
    • MAPK14
    • PRKCA
    • FRAP1
• Diabetes and Insulin Resistance
  • Background
    • Current Treatments
  • Kinase Targets
    • Kinase Targets of Metformin
    • GSK3B
    • PRKCB1
    • KDR
    • GCK
• Cardiovascular Disease
  • Background
    • Percutaneous Coronary Interventions
  • Kinase Targets
    • FRAP1
    • PDGFRA
    • MAPK14
• Other Applications

Chapter 6: Staking Claims to the Human Kinome

• Introduction
• Overview of Patents
• Role of Patents in the Biomedical Industry
• Patenting of Genes and Proteins
• The Kinase Patent Data Set
• Kinase Patent Activities
• Forward Citations
• Patent Assignees

Chapter 7: Market Considerations and Forecasts

• Introduction
• The Survey
  • Preliminary Remarks
  • Questions and Answers
  • Conclusions
• Kinase Drug R&D: Leading Indications
• Kinase Drug R&D: Leading Companies
• Kinase Drug R&D: Leading Targets
• Kinase Drug Companies, Indications, and Targets
• The World Pharmaceutical Market
• Kinase Markets
  • Cancer
    • Hematologic Cancers
    • Solid Tumors
  • Diabetes
  • Inflammation and Tissue Injury
  • Cardiovascular Disease
  • Central Nervous System
• Market Analysis and Forecasts
  • Cancer
  • Diabetes
  • Immunology/Inflammation
  • Cardiology
  • Central Nervous System
  • Geographical Markets

Chapter 8: Trends and Opportunities

• Kinases: The Big Picture
• Actual and Potential Targets of Kinase Drugs
• Checking the Commercial Pulse
• A Revolution in Cancer Treatment
• Drug Resistance: A Pressing Problem
• Single Versus Multiple Target Debate

Chapter 9: Company Profiles

Chapter 10: Appendices

• Appendix 1: Human Kinase Groups and Family Relationships
• Appendix 2: Kinase Companies by Product Portfolio (Summary)
• Appendix 3: Kinase Targets by Development Stage
• Appendix 4: Associations of Human Protein Kinases with Cancer Amplicons
• Appendix 5: Kinase-targeting Anticancer Drugs by Target
• Appendix 6: Kinase-Targeting Anticancer Drugs by Company
• Appendix 7: Kinase-Targeting Drugs by Indication
• Appendix 8: Associations of Human Protein Kinases with Non-Malignant Diseases
• Appendix 9: Kinases: Number of Drugs, Targets, and Indications by Company
• Appendix 10: Kinase Drugs: Actual, Potential, and Ancillary Targets
• Appendix 11: Kinases: Indications by Target
• Appendix 12: Kinases: Companies by Target
• Appendix 13: Kinases: Indications by Company

Table of Exhibits

• Exhibit 2.1 Hanks Classification of Protein Kinases (1995)
• Exhibit 2.2 Kinase Drugs by Development Stage
• Exhibit 2.3 Kinase Indications by Development Stage
• Exhibit 2.4 Kinase-targeted Drugs by Origin of Material
• Exhibit 6.1 Kinase Patents: Filing and Publication Dates
• Exhibit 6.2 Activity Analysis for US Kinase Patents, 2000-2006
• Exhibit 6.3 Top 30 Kinase Patents by Forward Citations (US Filings 2000-2006)
• Exhibit 6.4 Top 40 Kinase Patent Assignees
• Exhibit 6.5 Patenting Activities of the Top 15 Kinase Assignees
• Exhibit 7.1 List of Respondents' Organizations
• Exhibit 7.2 List of Respondents' Job Titles
• Exhibit 7.3 Job Functions of Survey Respondents
• Exhibit 7.4 Target Classes by Commercial Potential
• Exhibit 7.5 Kinase Target Subclasses by Commercial Potential
• Exhibit 7.6 Kinases: Multi-target vs Single-target?
• Exhibit 7.7 Kinase Inhibitors: MAbs vs Small Molecules?
• Exhibit 7.8 Origins of Kinase Inhibitors
• Exhibit 7.9 Indications for Kinase Inhibitors in Development
• Exhibit 7.10 Targets for Kinase Inhibitors in Development
• Exhibit 7.11 Role of Proteomic Profiling in the Development of Kinase-Targeted Drugs
• Exhibit 7.12 Indications for Kinase Inhibitors Currently on the Market
• Exhibit 7.13 Targets for Kinase Inhibitors Currently on the Market
• Exhibit 7.14 Most Promising Market Segments for Kinase Inhibitors
• Exhibit 7.15 Target Acquisition Strategies
• Exhibit 7.16 Target Development Strategies
• Exhibit 7.17 Kinase Drug Indications by Development Stage
• Exhibit 7.18 Company Product Portfolios by Development Stage
• Exhibit 7.19 Kinase Targets by Development Stage
• Exhibit 7.20 World Pharma Market by Region in 2005 and 2010
• Exhibit 7.21 World Pharma Market by Indication in 2005 and 2010
• Exhibit 7.22 Kinase Market Forecasts by Indication, 2005-2010
• Exhibit 7.23 Kinase Market Forecasts by Region, 2005-2010