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Handbook of
Experimental Pharmacology
Volume 167
Editor-in-Chief
K. Starke, Freiburg i. Br.
Editorial Board
G.V.R. Born, London
M. Eichelbaum, Stuttgart
D. Ganten, Berlin
F. Hofmann, Mnchen
B. Kobilka, Stanford, CA
W. Rosenthal, Berlin
G. Rubanyi, Richmond, CA
 Inhibitors of Protein Kinases
and Protein Phosphates
Contributors
D.R. Alexander, H.S. Andersen, N.R. Banner, R. Battistutta,
A.M. Berghuis, S.M. Blake, D. Bossemeyer, C. Breitenlechner,
D. L. Burk, A. Cheng, P. Cohen, S.W. Cowan-Jakob,
B.J. Druker, R. Engh, D. Fabbro, G. Fendrich, D.H. Fong,
P. Furet, M. Gaßel, J.D. Griffin, V. Guez, S. Herrero,
H. Hidaka, R.E. Honkanen, L.F. Iversen, C.B. Jeppesen,
S. Kumar, C. Kunick, C. Lampron, D.S. Lawrence, M. Leost,
O. Lozach, H. Lyster, P.W. Manley, L. Meijer, J. Mestan,
T. Meyer, N.P.H. Møller, S. Sarno, Y. Sasaki, S. Schmitt,
M. Shibuya, Y. Suzuki, M.L. Tremblay, N. Uetani,
A. Wakeling, M.H. Yacoub, G. Zanotti
Editors
Lorenzo A. Pinna and Patricia T.W. Cohen
Professor
Lorenzo A. Pinna
Universit di Padova
Dipartimento di Chimica Biologica
Via Trieste 75
Padova 35121
Italy
e-mail: lorenzo.pinna@unipd.it
Patricia T.W. Cohen, Ph.D.
Professor of Molecular Biology,
MRC Protein Phosphorylation Unit,
School of Life Sciences
University of Dundee
MSI/WTB Complex, Dow St.
Dundee, DD1 5EH
Scotland, U.K.
e-mail: p.t.w.cohen@dundee.ac.uk
With 95 Figures and 17 Tables
Library of Congress Control Number: 2004103428
ISSN 0171-2004
ISBN 3-540-21242-6
Springer Berlin Heidelberg New York
This work is subject to copyright. All rights are reserved, whether the whole or part of the material
is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broad-
casting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of
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Springer-Verlag is a part of Springer Science+Business Media
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Springer-Verlag Berlin Heidelberg 2005
Printed in Germany
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in the absence of a specific statement, that such names are exempt from the relevant protective laws
and regulations and free for general use.
Product liability: The publishers cannot guarantee the accuracy of any information about dosage
and application contained in this book. In every individual case the user must check such information
by consulting the relevant literature.
Editor: Dr. R. Lange, Heidelberg, Germany
Desk Editor: S. Dathe, Heidelberg, Germany
Production Editor: H. Schwaninger, Heidelberg, Germany
Cover design: design & production GmbH, Heidelberg, Germany
Typesetting: Strtz GmbH,Wrzburg, Germany
Printed on acid-free paper
27/3150 hs – 5 43210
Preface
Nearly all aspects of cell life (and death) are controlled by the phosphorylation of
proteins, which is catalysed by protein kinases (PKs) and reversed by protein
phosphatases (PPs). The role of PKs can be likened to that of interpreters, who
translate stimuli and signals into biochemical events. For this reason, PKs and
PPs are themselves interlinked and highly regulated, forming complex commu-
nicative networks. Not surprisingly, therefore, the deregulation of PKs results in
cell malfunction, eventually resulting in neoplastic growth and other diseases.
This makes PKs attractive targets for drugs not only to combat cancer, but also
for other global diseases, notably diabetes, inflammatory and infectious diseases,
stroke, hypertension and Alzheimers. Actually about half of all proto-oncogenes
so far identified encode PKs, and oncogenesis frequently results from the activa-
tion and/or overexpression of PKs. For example, overexpression of the epidermal
growth factor receptor tyrosine kinase is the cause of many cancers of epithelial
cell origin. In other instances, however, the link of PKs with neoplasia is not so
straightforward, and depends on defective interactions with cellular partners of
PKs, susceptibility to particular metabolic conditions, abnormal levels of other
regulatory components or the combination of several of these factors.
The attractiveness of PKs as targets is enhanced by the fact that they are en-
zymes, which are targetable molecules par excellence. Thus their biological activi-
ty can be turned off very easily and precisely by drugs that block the catalytic site.
Virtually all PKs belong to the largest single family of enzymes, numbering over
500 and accounting for almost 2% of the proteins encoded by the human genome.
They share similar catalytic domains that catalyse the transfer of phosphate from
ATP to serine, threonine or tyrosine residues in key regulatory proteins. Never-
theless, the structures of the catalytic domains of PKs are sufficiently distinctive
that it is possible to develop compounds that are highly selective for a particular
PK. Even the highly conserved binding site for the substrate ATP is surrounded
by structural elements with variable features that can be exploited for the design
of specific inhibitors, and most of the PK inhibitors currently undergoing human
clinical trials are of this type. Two PK inhibitors are already in clinical use for the
treatment of cancers (Gleevec and Iressa), while another is the immunosuppres-
sant of choice to prevent tissue rejection after organ transplantation (rapamycin).
At least 30 other PK inhibitors are undergoing human clinical trials to treat can-
cers and other diseases. These have the potential to provide a significant impact
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