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

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

Kinase Inhibitor Drugs covers a wide and comprehensive range of topics about kinase-targeted inhibitors in cancer therapy, one of the hottest drug targets in modern drug discovery. It brings together and summarizes important information and advances in the field to allow researchers and drug discoverers to easily discern the state of targeted cancer drug discovery. Complete with case studies of approved kinase inhibitors or those in late-phase clinical trials for cancer therapy, this is an ideal reference for pharmaceutical scientists developing small molecule and biotech drugs to treat cancer.

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

Preface ix

Contributors xiii

Part I Growth Factor Inhibitors: Vegfr2, Erbb2, And other Kinases 1

1 Discovery and Development of Sunitinib (SU11248): A Multitarget Tyrosine Kinase Inhibitor of Tumor Growth, Survival, and Angiogenesis 3
Connie L. Sun, James G. Christensen, and Gerald McMahon

2 Tykerb Discovery: A Dual EGFR and ERBB2 Tyrosine Kinase Inhibitor 41
Karen Lackey and G. Stuart Cockerill Copyrighted Material

3 Discovery of Pazopanib: A Pan Vascular Endothelial Growth Factor Kinase Inhibitor 57
Philip A. Harris and Jeffrey A. Stafford

4 Road to ABT-869: A Multitargeted Receptor Tyrosine Kinase Inhibitor 79
Michael Michaelides and Daniel H. Albert

5 Discovery of Motesanib 113
Andrew S. Tasker and Vinod F. Patel

6 Discovery of Brivanib Alaninate: A Dual Vascular Endothelial Growth Factor and Fibroblast Growth Factor Receptor Inhibitor 131
Rajeev S. Bhide and Joseph Fargnoli

7 Structure-Based Design and Characterization of Axitinib 167
Robert S. Kania

Part II Growth Factor Inhibitors: Mek Inhibitors 203

8 Road to PD0325901 and Beyond: The MEK Inhibitor Quest 205
Judith S. Sebolt-Leopold and Alexander J. Bridges

9 Discovery of Allosteric MEK Inhibitors 229
Eli Wallace and James F. Blake

Part III Cell Cycle Kinase Inhibitors: Aurora Kinase and Plk Inhibitors 253

10 Discovery of MK-0457 (VX-680) 255
Julian M. C. Golec

11 Discovery of PHA-739358 281
Daniele Fancelli and Jürgen Moll

12 Discovery of AZD1152: A Selective Inhibitor of Aurora-B Kinase with Potent Antitumor Activity 309
Kevin M. Foote and Andrew A. Mortlock

13 Case Study of Aurora-A Inhibitor MLN8054 333
Christopher F. Claiborne and Mark G. Manfredi

14 Discovery of GSK461364: A Polo-like Kinase 1 Inhibitor for the Treatment of Cancer 351
Kevin W. Kuntz and Kyle A. Emmitte

Part IV Related Special Topics 365

15 Pharmacogenomics of Dasatinib (Sprycel TM) 367
Fei Huang and Edwin A. Clark

16 Practical Use of Computational Chemistry in Kinase Drug Discovery 403
James M. Veal

17 Approaches to Kinase Homology Modeling: Successes and Considerations for the Structural Kinome 433
Victoria A. Feher and J. David Lawson

18 Fragment-Based Drug Discovery of Kinase Inhibitors 461
Daniel A. Erlanson

19 Protein Kinase Structural Biology: Methods and Strategies for Targeted Drug Discovery 485
Clifford D. Mol, Kengo Okada, and David J. Hosfield

Index 501