激酶標靶治療：開發產品線、挑戰及機會 是由出版商Insight Pharma Reports在2011年08月所出版的。
這份英文市場調查報告書價格從美金3195起跳。
激酶調製為生物醫療藥物產業中最受矚目的主題之一。美國目前已經許可了20種激酶抑制劑之銷售，最少也有250種激酶抑制劑正處於臨床評估階段，激酶嚴然成為了各種適應症所需之標靶寶庫。
本報告為，匯整激酶標靶之治療藥物開發趨勢、目前及新興應用於化合物開發之技術、參與激酶調製市場主要企業之計畫、各種激酶等級之特徵、產業挑戰及目前趨勢等，以下列摘要形式闡述。
實施概要
第1章 背景及科學概要：激酶為重要之細胞信號酵素
第2章 激酶及疾病：激酶為普遍之疾病標靶
- 獲確認與癌症之關聯性
- 受體酪氨酸、激酶標靶
- 非受體酪氨酸、激酶標靶
- Abl及Src
- 非受體酪氨酸、激酶標靶及免疫疾病
- 非受體酪氨酸、激酶標靶及癌症
- 癌症治療之絲氨酸、蘇氨酸激酶標靶
- Ras-Raf-MEK-ERK途徑
- PI3K-Akt-mTOR途徑
- PKA及PKC
- 細胞週期激酶
- 非癌症治療之絲氨酸、蘇氨酸激酶標靶
- MAP激酶
- NF-kB途徑
- 其他絲氨酸、蘇氨酸激酶標靶
第3章 開發中之激酶抑制劑：豐富標靶之開拓
- 激酶抑制劑之種類
- 受體酪氨酸、激酶抑制劑
- 非受體酪氨酸激酶抑製劑
- 癌症治療之絲氨酸、蘇氨酸激酶標靶
- 非癌症治療之絲氨酸、蘇氨酸激酶標靶
第4章 結論：激酶抑制劑開發之趨勢及挑戰
- 近年激酶抑制劑開發之趨勢
- 同領域之特殊挑戰
- 標靶相關性及差異性
- 耐藥性
- 臨床實驗設計
- 併用治療之使用
- 成本
參考
附錄：激酶名、縮寫
企業名錄
Abstract
The field of kinase modulation is one of the most active in the
biopharmaceutical industry. About 20 kinase inhibitors are approved for
marketing in the United States and at least another 250 are in clinical
evaluation. Kinases make up a veritable treasure trove of targets for a
variety of indications.
This report analyzes:
- The considerable array of therapeutic development efforts directed at
kinases
- Current and emerging technologies being applied to development of these
compounds
- The major companies and projects involved with kinase modulation
- How unique characteristics of different kinase classes impact therapeutic
development
- Current trends and major challenges faced by the industry
The role of kinases in cellular function and communication, coupled with their
sheer number, suggests that any disruption in their activity can have adverse
effects. Aberrant or inappropriate kinase activity has been associated with
many diseases, in particular those involving inflammatory or proliferative
responses. In addition to cancer and inflammatory disorders such as rheumatoid
arthritis, compromised kinase activity has been causally linked to diabetes,
cardiovascular disease, neurological disorders, and other conditions. The most
advanced compounds in clinical development target only a handful of the
best-characterized kinases. Beyond these kinase targets, hundreds more exist
that could provide sites for intervention in other disease processes.
Most, if not all, big pharma firms have programs in the area of kinase
modulation, and they are included among the leaders in the field.
Small-molecule kinase inhibitors are the most promising types of drugs in this
class because of their potential for oral delivery, the ease of fine-tuning
their chemical structure using classic and combinatorial chemistry techniques,
and their amenability to large-scale production. Monoclonal antibodies,
antisense, and RNA interference are also being targeted against kinases.
Kinase-Targeted Therapeutics: Development Pipelines, Challenges, and
Opportunities considers both small-molecule and biologic kinase-targeted
agents in development. We review the current R&D pipeline of products,
organized according to the major groups: the receptor and nonreceptor tyrosine
kinases; and the serine-threonine kinases.
A large proportion of late-stage clinical kinase inhibitor programs target
receptor tyrosine kinases. Although only 58 of the 518 human kinases fall into
this category, their role in controlling cellular growth and the fact that
they possess extracellular binding domains made them early and actively
explored targets for the development of compounds for cancer and other
proliferative diseases. Almost 40% of kinase inhibitors in clinical trials
fall into this category. Companies are, however, working to design improved
agents that target a wide range of combinations of these kinases. The role of
the PI3K-Akt-mTOR pathway in cancer is now also generating increased interest,
as many pharmaceutical companies are in the early stages of building programs
in this area.
While kinase modulation has shown itself to be a novel and promising approach
to treating disease, several limitations have become apparent in studies that
have been conducted to date. Kinase-Targeted Therapeutics: Development
Pipelines, Challenges, and Opportunities explores some of the challenges to
success in the field, including:
- Ensuring target relevance and specificity
- Overcoming resistance
- Designing clinical trials to maximize the response to a drug
- Addressing the high cost of novel therapeutics
About the Author: Mark C. Via, an editor at CTB International Publishing, has
more than 16 years of experience writing and editing for pharmaceutical trade
publications. He holds a BA in history from Williams College.
Table of Contents
Executive Summary
Chapter 1 BACKGROUND AND SCIENTIFIC OVERVIEW: KINASES ARE IMPORTANT CELLULAR SIGNALING ENZYMES
- 1.1. The Function of Kinases
- 1.2. Classifying KinasesTK
- TKL
- AGC
- CAMK
- CK1
- CMGC
- STE
- aPK
Chapter 2 KINASES AND DISEASE: KINASES ARE A UBIQUITOUS DISEASE TARGET
- 2.1. The Established Link to Cancer
- 2.2. Targeting Receptor Tyrosine KinasesThe Major Growth Factor Receptors
- Other Receptor Tyrosine Kinases
- 2.3. Targeting Nonreceptor Tyrosine KinasesAbl and Src
- Nonreceptor Tyrosine Kinases and Immune Disorders
- Nonreceptor Tyrosine Kinases and Cancer
- 2.4. Targeting Serine-Threonine Kinases for CancerThe Ras-Raf-MEK-ERK
Pathway
- The PI3K-Akt-mTOR Pathway
- PKA and PKC
- Cell Cycle Kinases
- 2.5. Targeting Serine-Threonine Kinases for Diseases Other than CancerMAP
Kinases
- NF-κB Pathway
- Other Serine-Threonine Kinases
Chapter 3 KINASE INHIBITORS IN DEVELOPMENT: TAPPING INTO A WEALTH OF TARGETS
- 3.1. Types of Kinase InhibitorsSmall Molecules
- 3.2. Receptor Tyrosine Kinase InhibitorsProfiles of Receptor Tyrosine
Kinase Inhibitors Approved for Marketing
- Herceptin (Trastuzumab) (1998)
- Iressa (Gefitinib) (2003)
- Erbitux (Cetuximab) (2004)
- Avastin (Bevacizumab) (2004)
- Tarceva (Erlotinib) (2004)
- Macugen (Pegaptanib) (2004)
- Lucentis (Ranibizumab) (2006)
- Sutent (Sunitinib) (2006)
- Nexavar (Sorafenib) (2005)
- Vectibix (Panitumumab) (2006)
- Tykerb (Lapatinib) (2007)
- Votrient (Pazopanib) (2009)
- Zactima (Vandetanib) (2011)
- EGFR Family
- Nimotuzumab
- Zalutumumab
- Necitumumab
- Rindopepimut
- RG7160 (GA201)
- CetuGEX (GT-MAB 5.2-GEX) and TrasGEX (GT-MAB 7.3-GEX)
- Pertuzumab
- Trastuzumab Emtansine
- MGAH22
- Afatinib (BIBW 2992)
- MM-121 and MM-111
- MEHD7945A
- Dacomitinib (PF-00299804) and Neratinib (HKI-272)
- Preclinical-Stage EGFR Family Inhibitors
- Split Kinase Domain Family
- Tivozanib (AV-951)
- CT-322 (BMS-844203; VEGFR2 Adnectin)
- Axitinib
- Cediranib (AZD2171)
- Telatinib and ACTB1003
- Intedanib (BIBF 1120)
- PLX3397
- Preclinical-Stage Split Kinase Domain Family Inhibitors
- Met
- Tivantinib (ARQ 197)
- Onartuzumab (MetMab; RG3638)
- Preclinical-Stage Met Inhibitors
- ALK
- Crizotinib (PF-02341066)
- Preclinical-Stage ALK Inhibitors
- IGF1R
- OSI-906
- Ganitumab (AMG 479)
- Other Preclinical-Stage Receptor Tyrosine Kinase Inhibitors
- 3.3. Nonreceptor Tyrosine Kinase InhibitorsProfiles of Nonreceptor
Tyrosine Kinase Inhibitors Approved for Marketing
- Gleevec (Imatinib Mesylate) (2001)
- Sprycel (Dasatinib) (2006)
- Tasigna (Nilotinib) (2007)
- Abl and Src Family
- Bosutinib
- Ponatinib
- Bafetinib
- XL228
- DCC-2036
- Preclinical-Stage Abl and Src Family Kinase Inhibitors
- JAK1 and JAK2
- Ruxolitinib (INCB18424) and LY3009104 (INCB28050)
- SB1518 and SB1578
- GLPG0634
- JAK3
- Tofacitinib
- VX-509
- Preclinical-Stage JAK3 Inhibitors
- Syk
- Fostamatinib (R788) and R343
- PRT062607
- BTK
- PCI-32765
- AVL-292
- Preclinical-Stage BTK Inhibitors
- 3.4. Serine-Threonine Kinase Inhibitors for CancerProfiles of Nonreceptor
Tyrosine Kinase Inhibitors Approved for Marketing
- Rapamune (Rapamycin; Sirolimus) (1999)
- Torisel (Temsirolimus) (2007)
- Zortress (Certican; Afinitor; Everolimus) (2009)
- Drug-Eluting Stents
- The Ras-Raf-MEK-ERK Pathway
- Vemurafenib (PLX4032; RG7204) and PLX5568
- GSK2118436
- XL281 (BMS-908662)
- RAF265
- iCo-007
- GSK1120212
- BAY 86-9766
- Array BioPharma' s MEK Inhibitors
- The PI3K-Akt-mTOR Pathway
- BKM120, BEZ235, and BYL719
- XL147 (SAR245408) and XL765 (SAR245409)
- PX-866
- GS 1101
- SF1126
- Perifosine (KRX-0401)
- AZD5363
- Ridaforolimus (AP23573; MK-8669)
- AZD8055 and AZD2014
- OSI-027
- INK128
- Preclinical-Stage PI3K-Akt-mTOR Inhibitors
- CDK
- Seliciclib (R-Roscovitine; CYC202)
- PD-0332991
- AT7519 and LEE011
- TG02 (SB1317)
- Aurora and PLK1
- AZD1152
- BI 811283
- MLN8237 and TAK-901
- AT9283
- Estybon (ON 01910.Na)
- TKM-PLK1
- Preclinical-Stage Aurora and PLK1 Inhibitors
- CHK and PIM1
- LY2603618 (IC83)
- CT100
- Preclinical-Stage CHK and PIM1 Inhibitors
- 3.5. Serine-Threonine Kinase Inhibitors for Diseases Other than CancerROCK
- AR-12286
- SLx-2119
- PKC-beta
- Ruboxistaurin (Arxxant)
- PKC-delta
- Delcasertib (KAI-9803)
- p38 MAP Kinase
- NF-κB Pathway
Chapter 4 CONCLUSIONS: TRENDS AND CHALLENGES IN KINASE INHIBITOR DEVELOPMENT
- 4.1. Recent Trends in Development of Kinase Inhibitors
- 4.2. Special Challenges in the FieldTarget Relevance and Specificity
- Resistance
- Trial Design
- Use in Combination Therapy
- Cost
References
Appendix KINASE NAMES AND ACRONYMS/ABBREVIATIONS
Company Index
在癌治療方面，PI3k-Akt-mTOR路徑引人注目
2011年09月20日
Global Information, Inc.已開始銷售Insight Pharma Reports所發行的報告書「Kinase-Targeted Therapeutics: Development Pipelines, Challenges, and Opportunities (激酶標靶治療：開發產品線、挑戰及機會)」
幾乎全部的大製藥公司都針對Kinase變調進行研究，在此領域成為主導者。小分子Kinase阻礙劑在這種藥劑中是最有前景者。因為此藥劑對口服給藥的可能性、以往使用型及使用組合化學技術的化學構造容易進行微調整，且更加兼備適合大量生產的特性。
單株抗體（monoclonal antibody）、antisense及RNA干涉再度成為是針對Kinase的標的。本報告書「Kinase標的療法：開發管道、課題和機會」，討論小分子及生物學Kinase標的製劑的開發。亦考察主要研究小組最新藥劑研究開發管道、受容體與非受容體酪胺酸激酶(tyrosine kinase)、以及絲胺酸 / 蘇胺酸激酶（Kinaseserine / threonine kinase）。多半情形都是後期臨床試驗的Kinase阻礙劑開發以受容體酪胺酸激酶(tyrosine kinase)作為標的。518人的Kinase中只有58人的包含在此範疇。然因細胞增殖控制功能和細胞外配合基（ligand）結合領域，能成為在初期階段明顯探知癌及其他增殖性疾病所造成化合物成長的標的。
臨床試驗時，約有40％的Kinase阻礙劑加入此範疇。然製藥公司的目標為能更廣範圍開發這些Kinase化合物作為標的藥劑。
癌治療時，PI3k-Akt-mTOR路徑現在引人注目，許多製藥公司都投入此領域進行初期階段的研究開發。
