Kinase Inhibitor Drugs / Edition 1

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Overview

A comprehensive resource on case studies of marketed kinase drugs and promising drug trials Since the discovery of protein kinase activity in 1954, the field of protein kinase drug discovery has advanced dramatically. With the ongoing clinical success of the Bcr-Abl kinase inhibitor Gleevec in the treatment of chronic myelogenous leukemia and seven additional marketed kinase inhibitor drugs, researchers have compelling evidence that kinase inhibitors can be highly efficacious in the treatment of diseases caused by aberrant activity of protein kinase. Currently more than 100 protein kinase inhibitors are in clinical development. In one comprehensive volume, the editors, Dr. Rongshi Li and Dr. Jeffrey Stafford, present timely and important case studies of marketed kinase drugs and several of the most advanced kinase inhibitors in clinical trials. Kinase Inhibitor Drugs includes:
• Case studies from leading investigators and experts in the field that provide firsthand accounts of kinase inhibitor discovery
• Current thinking on kinase structure, biochemistry, and signal transduction pathways
• Information on state-of-the-art technologies and tools such as structure-based and fragment-based drug discovery
• A lineup of clinical-phase growth factor receptor inhibitors
• Inhibitors of cell cycle kinases
• The discovery of allosteric inhibitors of MEK kinase
• Information on pharmacogenomics and its application to kinase inhibitor clinical development

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Editorial Reviews

From the Publisher
"In conclusion, I strongly recommend this book to anyone who is interested and new to the field of kinase inhibitors. Indeed, I believe this book should not merely sit on the shelves of kinase experts, but should be used frequently for reference." (ChemMedChem, 2010)

"Delivers what the title promises: a comprehensive treatment of drugs that inhibit kinases. ... Will be interesting to any chemist or biologist desiring a behind-the-scenes look at modern strategies of drug discovery and their practical applications to some challenging targets." (Journal of Medicinal Chemistry, April 2010)

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Product Details

Meet the Author

Rongshi Li, PhD, is an Associate Professor in the DrugDiscovery Department at H. Lee Moffitt Cancer Center and ResearchInstitute in Tampa, Florida.

Jeffrey A. Stafford, PhD, has led drug discovery researchat GlaxoSmithKline, Syrrx, and Takeda. He is a co-inventor of thetyrosine kinase inhibitor, pazopanib (Armala).

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Table of Contents

PREFACE.

CONTRIBUTORS.

PART I GROWTH FACTOR INHIBITORS: VEGFR2, ERBB2, AND OTHERKINASE.

1 Discovery and Development of Sunitinib (SU11248): AMultitarget Tyrosine Kinase Inhibitor of Tumor Growth, Survival,and Angiogenesis (Connie L. Sun, James G. Christensen, andGerald McMahon).

2 Tykerb Discovery: A Dual EGFR and ERBB2 Tyrosine KinaseInhibitor (Karen Lackey and G. Stuart Cockerill).

3 Discovery of Pazopanib: A Pan Vascular Endothelial GrowthFactor Kinase Inhibitor (Philip A. Harris and Jeffrey A.Stafford).

4 Road to ABT-869: A Multitargeted Receptor Tyrosine KinaseInhibitor (Michael Michaelides and Daniel H. Albert).

5 Discovery of Motesanib (Andrew S. Tasker and Vinod F.Patel).

6 Discovery of Brivanib Alaninate: A Dual Vascular EndothelialGrowth Factor and Fibroblast Growth Factor Receptor Inhibitor(Rajeev S. Bhide and Joseph Fargnoli).

7 S tructure-Based Design and Characterization of Axitinib(Robert S. Kania).

PART II GROWTH FACTOR INHIBITORS: MEK INHIBITORS.

8 Road to PD0325901 and Beyond: The MEK InhibitorQuest (Judith S. Sebolt-Leopold and Alexander J.Bridges).

9 Discovery of Allosteric MEK Inhibitors (Eli Wallaceand James F. Blake).

PART III CELL CYCLE KINASE INHIBITORS: AURORA KINASE AND PLKINHIBITORS.

10 Discovery of MK-0457 (VX-680) (Julian M. C.Golec).

11 Discovery of PHA-739358 (Daniele Fancelli and JürgenMoll).

12 Discovery of AZD1152: A Selective Inhibitor of Aurora-BKinase with Potent Antitumor Activity (Kevin M. Foote and AndrewA. Mortlock).

13 Case Study of Aurora-A Inhibitor MLN8054 (Christopher F.Claiborne and Mark G. Manfredi).

14 Discovery of GSK461364: A Polo-like Kinase 1 Inhibitor forthe Treatment of  Cancer (Kevin W. Kuntz and Kyle A.Emmitte).

PART IV RELATED SPECIAL TOPICS.

15 Pharmacogenomics of Dasatinib (Sprycel) (Fei Huang andEdwin A. Clark).

16 Practical Use of Computational Chemistry in Kinase DrugDiscovery (James M. Veal).

17 Approaches to Kinase Homology Modeling: Successes andConsiderations for the Structural Kinome (Victoria A. Feher andJ. David Lawson).

18 Fragment-Based Drug Discovery of Kinase Inhibitors (DanielA. Erlanson).

19 Protein Kinase Structural Biology: Methods and Strategies forTargeted Drug Discovery (Clifford D. Mol, Kengo Okada, and DavidJ. Hosfield).

INDEX.

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