蛋白激脢治療技術創新：企業產品線藥、應用治療、市場預測

Abstract

Kinases are a ubiquitous group of enzymes that catalyze the phosphoryl transfer reaction from a phosphate donor (usually ATP) to a receptor substrate, which can be protein, lipid, or a small molecule (e.g. sugar). Phosphorylation of protein substrates is a fundamental and reversible mechanism for regulating protein activity in eukaryotes. In addition to protein kinases, many other kinases play important roles in cellular phosphorylation reactions. Aberrant kinase activity has been directly implicated in the etiology of a wide spectrum of human pathologies. As a result of their importance, approximately 30% of current discovery and development spending focuses on kinases, especially in the fields of oncology, inflammation and metabolic diseases.

Table of Contents

Executive Summary

• Chapter 1 Kinases as drug targets
• Chapter 2 Small molecule kinase inhibitor discovery
• Chapter 3 Targeting kinases in cancer
• Chapter 4 Non-cancer applications of kinase drugs
• Chapter 5 Leading kinase drug originating companies
• Chapter 6 Market Analysis: Trends and Forecasts

Chapter 1 Kinases as drug targets

• Summary
• Introduction
  • Overview of human protein kinases
    • Classification schemes
• Kinases in signal transduction pathways
  • MAPK pathways
    • MAPK (ERK) pathway
    • JNK/SAPK pathway
    • MAPK14 pathway
    • PI3K/AKT signaling
  • JAK/STAT signaling
  • NFKB pathway
  • Insulin receptor signaling
  • 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
  • Monoclonal antibodies
  • Emerging biopharmaceuticals
• Kinase drug audit

Chapter 2 Small molecule kinase inhibitor discovery

• Summary
• Introduction
• Mechanisms of kinase inhibition
  • ATP competitive inhibitors
  • Irreversible inhibitors
  • Allosteric inhibitors
• Approaches to kinase inhibitor discovery
  • Traditional kinase inhibitor discovery
    • High-throughput screening of compound libraries
    • Lead optimization
  • Synthesis of inhibitor analogs
  • Structure-informed drug design
    • Structure-informed drug re-design
  • Fragment-based drug discovery
• Kinase inhibitor selectivity assays
  • Protein selectivity assays
    • Kinase activity assays
    • Kinase binding assays
  • Cellular selectivity assays
• Identifying substrates of kinases

Chapter 3 Targeting kinases in cancer

• Summary
• Overview of cancer
• Established and emerging therapies
• Therapeutic potential of kinase inhibition
  • Types of kinase targets
    • Mutationally-activated kinases
    • Kinases which sustain tumor growth
    • Kinases with roles in tumorigenesis
• Top 20 kinase targets
• Group: TK
  • ABL1 (Abl family)
    • Target characteristics
    • Inhibitors on the market
    • Inhibitors in development
  • EGFR and ERBB2 (EGFR family)
    • Target characteristics
    • Approaches to EGFR inhibition
    • Inhibitors on the market
    • Inhibitors in development
  • FLT3, KIT, PDGFRA, and PDGFRB (PDGFR family)
  • Target characteristics
  • Inhibitors on the market
  • Inhibitors in development
  • FLT1, FLT4, and KDR (VEGFR family)
    • Target characteristics
    • Inhibitors on the market
    • Inhibitors in development
  • JAK2 (JakA family)
    • Target characteristics
    • Drugs in development
  • MET (Met family)
    • Target characteristics
    • Agents in development
• Group: AGC
  • AKT1 (AKT family)
    • Target characteristics
    • Drugs in development
• Group: CMGC
  • CDC2 and CDK2 (CDK family; CDC2 subfamily)
    • Target characteristics
    • Drugs in development
• Group: Other
  • AURKA and AURKB (AUR family)
    • Target characteristics
    • Drugs in development
  • PLK1 (PLK family)
    • Target characteristics
    • Drugs in development
• Group: Atypical
  • Target characteristics
  • Inhibitors on the market
  • Inhibitors in development
• Dual specificity lipid/protein kinases
  • PIK3CA (PI3K)
    • Target characteristics
    • Inhibitors in development
• Future trends

Chapter 4 Non-cancer applications of kinase drugs

• Summary
• Introduction
• Chronic inflammation and kinases
  • Leading indications
  • Arthritis
  • Diabetes
  • Inflammation
  • Immunosuppression
  • Ophthalmology
  • Psoriasis
  • Pulmonary diseases
  • Cardiovascular
  • Myelodysplastic disorders
  • GI disorders
  • Pain
• Leading kinase targets
  • MAPK14
    • Target characteristics
    • Inhibitors in development
  • FRAP1
    • Target characteristics
    • Inhibitors on the market
    • Inhibitors in development
  • JAK3
    • Target characteristics
    • Inhibitors in development
  • NTRK1
    • Target characteristics
    • Inhibitors in development
  • ROCK1
    • Target characteristics
    • Inhibitors on the market
    • Inhibitors in development

Chapter 5 Leading kinase drug originating companies

• Summary/Introduction
• 5.1 Abbott Laboratories
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Ambit Biosciences Corp
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Amgen Inc
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Array BioPharma Inc
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• AstraZeneca plc
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Avila Therapeutics Inc
  • Company overview
  • Kinase drug pipeline
• Boehringer Ingelheim GmbH
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Bristol-Myers Squibb Co
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Cephalon Inc
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Deciphera Pharmaceuticals LLC
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Eli Lilly Co
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Exelixis Inc
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• GlaxoSmithKline plc
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Hoffmann-La Roche Ltd
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Johnson & Johnson
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Kyowa Hakko Kirin Co Ltd
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Novartis International AG
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Pfizer Inc
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline
• Sanofi-Aventis Group
  • Company overview
  • Kinase drug pipeline
• Wyeth
  • Company overview
  • Kinase-related collaborations (2005 onwards)
  • Kinase drug pipeline

Chapter 6 Market Analysis: Trends and Forecasts

• Summary
• Prevalence of targeted diseases
• Analyses and Forecasts by Type of Agent
  • Limus agents/mTOR inhibitors
    • Overview
    • Standalone mTOR inhibitors
    • Drug-eluting stents
    • Drug-eluting stent market
    • Sirolimus-eluting stents
    • Everolimus- and zotarolimus-eluting stents
    • Sales trends in mTOR inhibitors
    • Forthcoming mTOR inhibitors
  • EGFR Family inhibitors
    • Overview
    • Trastuzumab
    • Erlotinib
    • Cetuximab
    • Gefitinib
    • Panitumumab
    • Lapatinib
    • Nimotuzumab
    • Sales trends in EGFR Family inhibitors
    • Forthcoming EGFR Family Inhibitors
  • ABL/FLT3 Group Inhibitors
    • Overview
    • Imatinib
    • Dasatinib
    • Nilotinib
    • Sales trends in ABL1/FLT3 Family Inhibitors
    • Forthcoming ABL1/FLT3 Family Inhibitors
  • VEGFR Family
    • Overview
    • Sunitinib
    • Sorafenib
    • Sales trends in VEGFR Family inhibitors
    • Forthcoming VEGFR Family Inhibitors
  • Other launched agents
    • Overview
    • Fasudil
    • Pirfenidone
    • Sales trends of other agents
    • Other forthcoming agents
• Company sales and trends
• Patenting trends
• Appendix 1 Kinase-related targets and their abbreviations
• Appendix 2 Other abbreviations and acronyms
• Appendix 3 Research Methodology
• Index

List of Figures

• Figure 1.1: Leading kinase-targeted drug applications
• Figure 1.2: Kinase target landscape
• Figure 6.3: Kinase originator market shares

List of Tables

• Table 1.1: Human Kinase Gene Audit
• Table 1.2: Hanks Classification of Protein Kinases (1995)
• Table 1.3: Hanks Classification of Protein Kinases (1995) (continued)
• Table 1.4: Kinase Agents by Development Stage
• Table 1.5: Kinase Drugs by Product Type
• Table 1.6: Leading developers of therapeutic kinase-targeted drugs
• Table 1.7: Kinase Agonists and Stimulants
• Table 3.8: Kinases implicated in human cancer
• Table 3.9: Kinases implicated in human cancer (continued)
• Table 3.10: Top 20 Kinase Targets in Cancer
• Table 3.11: Overview of ABL1-targeted agents in cancer
• Table 3.12: Overview of ABL1-targeted agents in cancer (continued 1)
• Table 3.13: Overview of ABL1-targeted agents in cancer (continued 2)
• Table 3.14: Overview of EGFR-targeted agents in cancer
• Table 3.15: Overview of EGFR-targeted agents in cancer (Phase III and above)
• Table 3.16: Overview of EGFR-targeted agents in cancer (Phase II)
• Table 3.17: Overview of EGFR-targeted agents in cancer (Phase I)
• Table 3.18: Overview of EGFR-targeted agents in cancer (Preclinical)
• Table 3.19: Overview of ERBB2-targeted agents in cancer (Phase III and above)
• Table 3.20: Overview of ERBB2-targeted agents in cancer (Phase II)
• Table 3.21: Overview of ERBB2-targeted agents in cancer (Phase I and Preclinical)
• Table 3.22: Overview of FLT3-targeted agents in cancer (Launched)
• Table 3.23: Overview of FLT3-targeted agents in cancer (Phase II and III)
• Table 3.24: Overview of FLT3-targeted agents in cancer (Phase I and II)
• Table 3.25: Overview of FLT3-targeted agents in cancer (Preclinical and Phase I)
• Table 3.26: Overview of KIT-targeted agents in cancer
• Table 3.27: Overview of KIT-targeted agents in cancer (Continued 1)
• Table 3.28: Overview of KIT-targeted agents in cancer (Continued 2)
• Table 3.29: Overview of KIT-targeted agents in cancer (Continued 3)
• Table 3.30: Overview of KIT-targeted agents in cancer (Continued 4)
• Table 3.31: Overview of KIT-targeted agents in cancer (Continued 4)
• Table 3.32: Overview of PDGFRA-targeted agents in cancer
• Table 3.33: Overview of PDGFRA-targeted agents in cancer (Continued 1)
• Table 3.34: Overview of PDGFRA-targeted agents in cancer (Continued 2)
• Table 3.35: Overview of PDGFRA-targeted agents in cancer (Continued 3)
• Table 3.36: Overview of PDGFRB-targeted agents in cancer (Phase II and Phase III)
• Table 3.37: Overview of PDGFRB-targeted agents in cancer (Preclinical and Phase I)
• Table 3.38: Overview of FLT1-targeted agents in cancer
• Table 3.39: Overview of FLT1-targeted agents in cancer (Continued 1)
• Table 3.40: Overview of FLT1-targeted agents in cancer (Continued 2)
• Table 3.41: Overview of FLT1-targeted agents in cancer (Continued 3)
• Table 3.42: Overview of FLT4-targeted agents in cancer
• Table 3.43: Overview of FLT4-targeted agents in cancer (Continued 1)
• Table 3.44: Overview of FLT4-targeted agents in cancer (Continued 2)
• Table 3.45: Overview of KDR-targeted agents in cancer
• Table 3.46: Overview of KDR-targeted agents in cancer (Continued 1)
• Table 3.47: Overview of KDR-targeted agents in cancer (Continued 2)
• Table 3.48: Overview of KDR-targeted agents in cancer (Continued 3)
• Table 3.49: Overview of KDR-targeted agents in cancer (Continued 4)
• Table 3.50: Overview of KDR-targeted agents in cancer (Continued 5)
• Table 3.51: Overview of JAK2-Targeted Agents in Cancer
• Table 3.52: Overview of JAK2-Targeted Agents in Cancer (continued)
• Table 3.53: Overview of MET-Targeted Agents in Cancer (continued)
• Table 3.54: Overview of MET-Targeted Agents in Cancer (continued)
• Table 3.55: Overview of AKT1-Targeted Agents in Cancer (continued)
• Table 3.56: Overview of AKT1-Targeted Agents in Cancer (continued)
• Table 3.57: Overview of CDC2-Targeted Agents in Cancer
• Table 3.58: Overview of CDK2-Targeted Agents in Cancer
• Table 3.59: Overview of CDK2-Targeted Agents in Cancer (continued)
• Table 3.60: Overview of AURKA-Targeted Agents in Cancer
• Table 3.61: Overview of AURKA -Targeted Agents in Cancer (continued)
• Table 3.62: Overview of AURKB -Targeted Agents in Cancer
• Table 3.63: Overview of PLK1 -Targeted Agents in Cancer
• Table 3.64: Overview of FRAP1 -Targeted Agents in Cancer
• Table 3.65: Overview of FRAP1 -Targeted Agents in Cancer (Continued 1)
• Table 3.66: Overview of FRAP1 -Targeted Agents in Cancer (Continued 2)
• Table 3.67: Overview of PIK3CA -Targeted Agents in Cancer
• Table 3.68: Overview of PIK3CA -Targeted Agents in Cancer (Continued)
• Table 4.69: Kinase-Targeted Agents With Anti-Arthritic Applications
• Table 4.70: Kinase-Targeted Agents With Anti-Arthritic Applications (continued 1)
• Table 4.71: Kinase-Targeted Agents With Anti-Arthritic Applications (continued 2)
• Table 4.72: Kinase-Targeted Agents With Anti-Arthritic Applications (continued 3)
• Table 4.73: Kinase-Targeted Agents With Anti-Arthritic Applications (continued 4)
• Table 4.74: Kinase-Targeted Agents With Anti-Arthritic Applications (continued 5)
• Table 4.75: Kinase-Targeted Agents With Diabetes Applications
• Table 4.76: Kinase-Targeted Agents With Diabetes Applications (continued 1)
• Table 4.77: Kinase-Targeted Agents With Diabetes Applications (continued 2)
• Table 4.78: Kinase-Targeted Agents With Inflammatory Applications
• Table 4.79: Kinase-Targeted Agents With Inflammatory Applications (Continued 1)
• Table 4.80: Kinase-Targeted Agents With Inflammatory Applications (Continued 2)
• Table 4.81: Kinase-Targeted Agents With Immunosuppresive Applications
• Table 4.82: Kinase-Targeted Agents With Immunosuppresive Applications (continued)
• Table 4.83: Kinase-Targeted Agents With Ophthalmological Applications
• Table 4.84: Kinase-Targeted Agents With Ophthalmological Applications (continued)
• Table 4.85: Kinase-Targeted Agents With Psoriasis Applications (continued)
• Table 4.86: Kinase-Targeted Agents With Psoriasis Applications (continued)
• Table 4.87: Kinase-Targeted Agents With PulmonaryApplications (Launched)
• Table 4.88: Kinase-Targeted Agents With PulmonaryApplications (Phase I-III)
• Table 4.89: Kinase-Targeted Agents With PulmonaryApplications (Preclinical)
• Table 4.90: Kinase-targeted agents with cardiovascular applications
• Table 4.91: Kinase-targeted agents with cardiovascular applications (continued)
• Table 4.92: Kinase-targeted agents with myelodysplastic disorder applications
• Table 4.93: Kinase-targeted agents with myelodysplastic disorder applications (continued)
• Table 4.94: Kinase-targeted agents with myelodysplastic disorder applications (continued 2)
• Table 4.95: Kinase-targeted agents with myelodysplastic disorder applications (continued 3)
• Table 4.96: Kinase-targeted agents with GI disorder applications
• Table 4.97: Kinase-targeted agents with GI disorder applications
• Table 5.98: Overview of Abbott' s kinase pipeline by status
• Table 5.99: Overview of Ambit Biosciences' Kinase Pipeline by Status
• Table 5.100: Overview of Amgen' s kinase pipeline by status
• Table 5.101: Overview of Array BioPharma' s kinase pipeline by status
• Table 5.102: Overview of AstraZeneca' s kinase pipeline by status
• Table 5.103: Overview of Avila Therapeutics' kinase pipeline by status
• Table 5.104: Overview of Boehringer Ingelheim' s kinase pipeline by status
• Table 5.105: Overview of Bristol-Myers Squibb' s (BMS) kinase pipeline by status
• Table 5.106: Overview of Cephalon' s kinase pipeline by status
• Table 5.107: Overview of Deciphera Pharmaceuticals' kinase pipeline by status
• Table 5.108: Overview of Eli Lilly' s kinase pipeline by status
• Table 5.109: Overview of Eli Lilly' s kinase pipeline by status (continued)
• Table 5.110: Overview of Exelixis' kinase pipeline by status
• Table 5.111: Overview of Exelixis' kinase pipeline by status
• Table 5.112: Overview of Hoffmann-La Roche' s kinase pipeline by status
• Table 5.113: Overview of Johnson & Johnson' s kinase pipeline by status
• Table 5.114: Overview of Kyowa Hakko Kirin' s kinase pipeline by status
• Table 5.115: Overview of Novartis' kinase pipeline by status
• Table 5.116: Overview of Novartis' kinase pipeline by status (continued)
• Table 5.117: Overview of Pfizer' s kinase pipeline by status
• Table 5.118: Overview of Sanofi-Aventis' kinase pipeline by status
• Table 5.119: Overview of Wyeth' s kinase pipeline by status
• Table 6.120: World Prevalence Of Diseases
• Table 6.121: World Pharma Market by Indication (US$m), 2008-2013
• Table 6.122: World Pharma Market by Region (US$m), 2008-2013
• Table 6.123: Kinase Drug Analysis (in 2007-2008) and Forecasts, 2009-2013 ($USm)
• Table 6.124: Kinase Inhibitors by Geography ($USm), 2008 and 2013
• Table 6.125: Manufacturer Analysis (2008) and Forecasts (US$m), 2009-2013
• Table 6.126: Major Kinase Patent Indications
• Table 6.127: Leading Kinase Patent Assignees