Inhibitors of Cyclin-dependent Kinases as Anti-tumor Agents (Enzyme Inhibitors Series)

476 Pages·2006·12.55 MB·English

by  Paul J. Smith

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Inhibitors(cid:1)of(cid:1)Cyclin-dependent
Kinases(cid:1)as(cid:1)Anti-tumor(cid:1)Agents
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CRC Enzyme Inhibitors Series
Series Editors
H. John Smith and Claire Simons
Cardiff University
Cardiff, UK
Carbonic Anhydrase: Its Inhibitors and Activators
Edited by Claudiu T. Supuran, Andrea Scozzafava and Janet Conway
Enzymes and Their Inhibition: Drug Development
Edited by H. John Smith and Claire Simons
Inhibitors of Cyclin-dependent Kinases as Anti-tumor Agents
Edited by Paul J. Smith and Eddy W. Yue
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CRC Enzyme Inhibitors Series
Inhibitors(cid:1)of(cid:1)Cyclin-dependent
Kinases(cid:1)as(cid:1)Anti-tumor(cid:1)Agents
Edited(cid:1)by
Paul(cid:1)J.(cid:1)Smith
Eddy(cid:1)W.(cid:1)Yue
Boca Raton London New York
CRC is an imprint of the Taylor & Francis Group,
an informa business
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CRC Press
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International Standard Book Number-10: 0-8493-3774-7 (Hardcover)
International Standard Book Number-13: 978-0-8493-3774-1 (Hardcover)
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Library of Congress Cataloging-in-Publication Data
Inhibitors of cyclin-dependent kinases as anti-tumor agents / edited by Paul J.
Smith, Eddy W. Yue.
p.cm. -- (Enzyme inhibitors ; 3)
Includes bibliographical references (p. ).
ISBN 0-8493-3774-7 -- ISBN 1-4200-0540-5
1. Cyclin-dependent kinases--Inhibitors. 2. Cyclin-dependent
kinases--Inhibitors--Therapeutic use--Testing. 3. Cancer--Chemotherapy. I.
Smith, Paul J. (Paul James), 1953- II. Yue, Eddy W. III. Series.
QP609.C93I54 2006
616.99’407--dc22 2006045588
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
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Series Preface
One approach to the development of drugs as medicines, which has g ained consi-
derable success over the past tw o decades, involves inhibition of the acti vity of a
target enzyme in the body or invading parasite by a small molecule inhibitor, leading
to a useful clinical effect.
The CRC Enzyme Inhibitor Series consists of an xepanding series of monographs
on this aspect of drug de velopment, providing timely and in-depth accounts of
developing and future targets that collectively embrace the contributions of medicinal
chemistry (synthesis, design), pharmacology and toxicology, biochemisty, physiol-
ogy, and biopharmaceutics necessary in the de velopment of novel pharmaceutics.
H. John Smith
Claire Simons
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Preface
The mechanisms for controlling when and ho w a eukaryotic cell di vides are funda-
mental to the biology of multicellular or ganisms. Abnormal regulation can provide a
driver for disease processes, not the least, cancer. The aim of this volume is to provide
an overview of the key regulator molecules — the cyclin-dependent kinases (CDKs)
— as molecular and functional entities, together with both their in volvement in dif-
ferent disease processes and their potential for pharmacological modulation.
The cell cycle is at the heart of the rationale for this area of intensi ve endeavor in
basic research and drug development. The cell cycle comprises the transitions that a cell
undergoes to achieve proliferation. The central importance of the cell c ycle regulation
machinery was recognized in the awarding of the Nobel Prize in Physiology or Medicine
for 2001 to Leland Hartwell, Paul Nurse, and Timothy Hunt for their discoveries in the
fields of cell ycle genes, checkpoint controls, the CDKs, and the c yclins. In the mid-
1970s, Paul Nurse discovered the archetypal CDK gene (CDC2) in the Schizosaccharo-
myces pombe yeast, later isolating the corresponding gene in humans (CDK1), the
function of this CDK being highly conserv ed during evolution. The chapters in this
volume touch upon the cell cycle regulatory genes and their physiological inhibitors, the
cyclin-dependent kinase inhibitors or CDKIs, distinct from the small molecule inhibitors
that by chance or design ha ve been found to impact upon CDK function. This volume
was prompted by the realization that we are at a critical point in time for our understand-
ing of the availability, advantages, and drawbacks of the CDKs as therapeutic targets for
small molecules. Accordingly, the volume offers a current perspective on where we stand
in terms of the success of the agents de veloped so far, the possibility of new routes to
more selective inhibitors and our growing appreciation of the critical issues for therapy.
This book partitions its chapters into four sections, addressing in sequence the
integration of cell c ycle control pathways and the opportunities for tar geting, the
targets of inhibitors and their evaluation, the chemistry of the pharmacological CDK
inhibitors, and finally a therapeutic perspect ve and horizon scan.
The first s ven chapters, covering two sections, set the scene for the chemistry
focus. The opening chapter by P aul Smith, Emeline Furon, and Rachel Errington
provides an overview of cell cycle dynamics and the challenges for CDK targeting,
highlighting issues raised in more detail in other chapters with a critical discussion
on the problem of metastatic disease control. Functional re gulation of the physio-
logical CIP/KIP CDK inhibitors is reviewed by Mong-Hong Lee and Ruiying Zhao,
revealing the recently discovered molecular regulation of the CKI family members.
The use of mouse models to study the in vivo function of CDKs in normal homeo-
stasis and tumor de velopment is described by Marcos Malumbres, Pierre Dub us,
and Sagrario Ortega. The elegant studies overviewed reveal how the absence of what
are often regarded as key regulators can still be compatible with cellular survi val,
underlining the functional buffering that is programmed into mammalian cells. This
redundancy has clear implications for therapeutic interv ention in cancer.
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Moving the focus away from cancer, Martin Crook and Manfred Boehm mak e
the case for understanding the molecular mechanisms of gro wth control in cardio-
vascular cells and how this can lead to the de velopment of exciting new molecular
therapies for heart and vascular diseases. Stéphane Bach, Marc Blondel, and Laurent
Meijer contribute a chapter on the e valuation of CDK inhibitor selectivity, with an
insightful review of methodologies from affinity chromatograp y to yeast genetics.
Sachin Mahale and Bhabatosh Chaudhuri bring a focus to bear on cyclin-dependent
kinase 4, exploring its selective inhibition in vivo and in vitro by designed small
molecules. Ursula Schulze-Gahman and Sung-Hou Kim pro vide an excellent over-
view of the structural biology of the CDKs. The structures of CDKs are co vered
from their apoenzymes to activated CDK/cyclin complexes to CDK/inhibitor com-
plexes. Their analysis of the structural basis for CDK specificity pr vides an impor-
tant foundation for the chemistry section.
The focus of the third section is the design, development, and chemistry of small
molecule CDK inhibitors. The chapters in this section range from overviews of late-
stage compounds that are already in clinical development to the early-stage discovery
of new chemical entities with a capacity to inhibit the CDKs. At the beginning of
this section, Adrian Senderowicz reviews two of the better known CDK inhibitors,
fl vopiridol (a fl vonoid) and UCN-01 (a staurosporine analog), with an emphasis
on their mechanism of action and results in clinical trials.T he following two chapters
also focus on well-kno wn inhibitors of CDKs. Laurent Meijer and co- authors
provide a comprehensive review of roscovitine, a purine that was discovered using
a classical medicinal chemistry approach, whereas Conrad K unick and co-authors
describe the discovery of the no vel paullones found through the Antitumor Drug
Screening Program at the National Cancer Institute. In the first of s veral reviews
by groups in the pharmaceutical industry , John Hunt addresses the disco very and
development of BMS-387032, a potent and no vel aminothiazole CDK inhibitor
currently in clinical study. The next chapter focuses on the oxindole class of CDK
inhibitors reviewed by Philip Harris who notes the existence of this pharmacophore
has been studied by a number of research groups in both pharmaceutical companies
and academia. The indenopyrazoles, reviewed by David Carini, Catherine Burton,
and Steven Seitz, is another potent and no vel class of CDK inhibitors disco vered
from high-throughput screening and optimized to compounds with a good biological
profile
The remaining chapters in the chemistry section illustrate the e xtensive SAR
knowledge that is generated from groups in the pharmaceutical industry intent on
discovering inhibitors of CDKs with the right balance of acti vity, selectivity, and
pharmacological properties. Guoxin Zhu describes the de velopment of indolocarba-
zoles which are in the same structural class as UCN-01 and staurosporine. P aolo
Pevarello and Anna Vulpetti review the use of p yrazoles as potent and selecti ve
inhibitors of CDKs. Jay Markwalder and Steven Seitz end this section with a re view
of the pyrazolopyrimidines, another unique class of inhibitors also disco vered from
high-throughput screening. The diversity of the compounds and pharmacophores
explored in this section highlights the opportunities for disco very of novel inhibitors.
As a number of CDK inhibitors ha ve now entered clinical trials, a report on
their current status is provided by Lloyd Kelland, with an evaluation of their potential
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use in combination with various anticancer cytotoxic agents. Chapter 17 reveals the
challenges faced by the therapeutic deployment of small molecule inhibitors, reso-
nating with the issues raised in other chapters. Finally, in Chapter 18, Richard Pestell
and co-authors provide a perspective on the future of developing CDK inhibitors as
anticancer agents. The design and discovery of small molecule inhibitors of CDK
has focused on targeting the ATP-binding site and finding compounds that compet
with ATP. The authors point to the use of detailed structural information of
CDK/cyclin complexes as one w ay to develop better inhibitors. The book affirm
the importance of selectivity with respect to inhibitor design, a matter made more
critical by the increasing number of functions ascribed to CDK/c yclin complexes.
An intriguing outlook is the potential for CDK inhibitors to regulate the local tumor
microenvironment, diverting therapeutic attention away from direct targeting of the
cancer cell, with the prospect of reducing microenvironmental signals that promote
tumor progression. New concepts promise solutions to the therapeutic challenges
and conflicts considered in the opening chapter of the olume.
Our primary aim as editors w as to provide readers — from research chemists
to clinicians — with a contemporary position to vie w the importance of rational
drug design and knowledge-based therapeutics in relation to these exceptional kinase
targets. The extensively referenced chapters dra w upon perspectives and insights
from expert groups in academia, go vernment institutions, and the pharmaceutical
industry to meet this brief.
Paul J. Smith
Cardiff, Wales, United Kingdom
Eddy W. Yue
Wilmington, Delaware
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The Editors
Paul J. Smith has been active in the fields of D A repair,
drug development, cytometry, and imaging technologies for
more than 20 years. His current academic research focuses
on the cell cycle and anticancer drugs, imaging technologies,
and mathematical modeling of complex biological systems.
He received his Ph.D. in cellular radiobiology from Manches-
ter University. After fellowship positions at the Atomic
Energy of Canada Chalk Ri ver Nuclear Laboratories in
Ontario, including support by the U.S. National Cancer Insti-
tute, he returned to the United Kingdom, becoming a senior
scientist with the Medical Research Council at the MRC
Centre in Cambridge. There he pursued basic research in a
clinical oncology unit. In 1995 he was appointed to the Chair of Cancer Biology at the
University of Wales College of Medicine in Cardif f, incorporated in 2004 into the
merged Cardiff University. Professor Smith is author of numerous research papers and
is the senior editor of the multiauthor book DNA Recombination and Repair . He is
cofounder and director of a spin-out company serving the biotechnology, drug screening,
and healthcare market sectors. As the principal investigator in the U.K. Optical Biochips
Consortium, he also leads an interdisciplinary ef fort to develop microtechnologies in
the fields of drug screening and diagnostics. He is a member of U.K. Research Councisl
review and expert panels and a member of journal editorial boards. He has represented
national bioscience interests in the United States and the F ar East, and has promoted
the public understanding of science in open lectures and the broadcast media.
Eddy W. Yue attended the University of California, Berke-
ley, as an undergraduate where he quickly de veloped a fond-
ness for synthetic or ganic chemistry. During his time at UC
Berkeley, he performed independent research at Lawrence Ber-
keley National Laboratory in the Division of Nuclear Medicine
where he synthesized compounds for positron emission tomog-
raphy studies. Dr. Yue received his B.S. in chemistry in 1991
and then entered the graduate program atT he Scripps Research
Institute in La Jolla, California, where he worked with Prof.
K. C. Nicolaou. He was involved in the total synthesis of the
natural product Zaragozic Acid A, a squalene synthase inhibitor
that contains a f ascinating highly oxygenated core structure.
He also contrib uted to the de velopment of no vel reactions in the areas of enediyne
chemistry and polyether macrocyclic natural products. In 1996 he recei ved his Ph.D.
degree and then joined the medicinal chemistry department at The DuPont Merck