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

Rongshi Li, PhD, is an Associate Professor in the Drug
Discovery Department at H. Lee Moffitt Cancer Center and Research
Institute in Tampa, Florida.

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).

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.

CONTRIBUTORS.

PART I GROWTH FACTOR INHIBITORS: VEGFR2, ERBB2, AND OTHER
KINASE.

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

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

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

4 Road to ABT-869: A Multitargeted Receptor Tyrosine Kinase
Inhibitor (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 Endothelial
Growth 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 Inhibitor
Quest (Judith S. Sebolt-Leopold and Alexander J.
Bridges).

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

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

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

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

12 Discovery of AZD1152: A Selective Inhibitor of Aurora-B
Kinase with Potent Antitumor Activity (Kevin M. Foote and Andrew
A. 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 for
the Treatment of Cancer (Kevin W. Kuntz and Kyle A.
Emmitte).

PART IV RELATED SPECIAL TOPICS.

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

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

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

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

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

INDEX.