Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 7, Number 14, 2007
Contents
Targeting Protein Kinases in Drug Discovery
and Medicinal Chemistry
Guest Editor: Jeffrey Jie-Lou Liao
Editorial Pp. 1331
Molecular Targeting of Protein Kinases to Optimize
Selectivity and Resistance Profiles of Kinase Inhibitors
Pp. 1332-1335
Jeffrey Jie-Lou Liao
[Abstract]
The Role of Halogen Bonding in Inhibitor Recognition
and Binding by Protein Kinases Pp. 1336-1348
Andrea Regier Voth and P. Shing Ho
[Abstract]
Recent Progress in the Development of ATP-Competitive
and Allosteric Akt Kinase Inhibitors Pp. 1349-1363
Craig W. Lindsley, Stanley F. Barnett, Melissa Yaroschak,
Mark T. Bilodeau and Mark E. Layton
[Abstract]
Recent Advances of MEK Inhibitors and Their Clinical
Progress Pp. 1364-1378
John (Yuan) Wang, Keith M. Wilcoxen, Kenichi Nomoto, and
Sara Wu
[Abstract]
Molecular Design and Clinical Development of VEGFR
Kinase Inhibitors Pp. 1379-1393
Haizhen Zhong and J. Phillip Bowen
[Abstract]
Targeting Protein Multiple Conformations: A Structure-Based
Strategy for Kinase Drug Design Pp. 1394-1407
Jeffrey Jie-Lou Liao and Robert C. Andrews
[Abstract]
A Comparison of Physicochemical Property Profiles
of Marketed Oral Drugs and Orally Bioavailable Anti-Cancer
Protein Kinase Inhibitors in Clinical Development Pp.
1408-1422
Adrian L. Gill, Marcel Verdonk, Robert G. Boyle and Richard
Taylor
[Abstract]
Molecule
of Month Pp. 1423
Abstracts
[Back to top]
Editorial
Human kinome contains 518 members. Over 150 protein kinases
are associated with various diseases including cancer. Protein
kinase drug discovery now is a hot area in the pharmaceutical
industry. Currently, it is estimated that approximately 1/4-1/3
of drug discovery programs target protein kinases. However,
identification of highly selective small-molecule inhibitors
with suitable PK properties for a protein kinase target frequently
presents a challenging problem in a kinase drug discovery
program, mostly because of highly conserved nature of the
catalytic domain in sequence and structure. Despite a significant
number of disease-associated protein kinases, only a limited
number of kinases have been successfully targeted by seven
FDA-approved small-molecule drugs so far, highlighting the
need for novel strategies and methods in the field.
This issue reviews most recent advances in molecular targeting
protein kinases in drug discovery and medicinal chemistry.
The issue starts with the review of the major concerns and
the rationalization of the serendipity in the history of protein
kinase drug discovery. In this paper, a novel picture where
the selectivity profile of a protein kinase inhibitor can
be correlated with its resistant mutation profile is provided.
This analysis could offer a potential for a future kinase
program to optimize the profile of a lead compound with the
ability to induce resistant mutation in the target, which
is a major obstacle in kinase-targeted cancer therapy, in
early-stage development. Halogen bonding has been known in
organic chemistry since the 1950s. However, it seems not to
be widely recognized by medicinal chemists although halogen
bonding interaction has been used empirically in some drug
discovery programs. Professor P. Shing Ho and his group re-discovered
the significance of this type of interaction in protein-ligand
systems guided by the first principle recently. In this issue,
Andrea Regier Voth and P. Shing Ho investigate the role of
halogen bonding in inhibitor recognition and binding by protein
kinases. The overexpression of the serine/threonine kinase
Akt in the PI3K/Akt pathway is implicated in a number of human
cancers. Drs. Lindsley, Layton and their colleagues from Merck
Research Laboratories describe recent advances in the development
and biological evaluation of small-molecule inhibitors for
this promising target. The RAS/RAF/MEK/ERK signaling pathway
has been a major clinical focus in oncology research in recent
years. Drs. Wang, Wilcoxen, Nomoto and Wu review recent advances
of MEK inhibitors targeting this pathway. VEGFR-associated
vascular angiogenesis plays a key role in many solid tumors.
The review of Professor Bowen and Dr. Zhong discusses most
recently developed VEGFR inhibitors. As targeting a highly
specific inactive protein kinase conformation has become a
major approach to design kinase inhibitors with a high degree
of selectivity, binding a kinase target into multiple conformations
is emerging as a key method to develop inhibitors with distinct
but clinical useful profiles. Drs. Liao and Andrews present
this structure-based strategy in detail in their article.
Dr. Gill and his colleagues demonstrate in their paper that
protein kinase small-molecule inhibitors have physicochemical
property profiles distinguished from other types of marketed
oral drugs.
The articles in this issue contributed from six research groups
cover important aspects of molecular targeting of protein
kinases, providing the structure-based strategy, novel insight
into molecular recognition of protein kinases and updates
for the development of kinase inhibitors for important signal
transduction pathways. It is my hope that these contributions
will benefit R & D in the field. I would like to thank
all authors who contribute to this issue and, in particular,
Dr. Allen B. Reitz for inviting me to be Guest Editor of this
issue.
Dr. Jeffrey Jie-Lou Liao
Guest Editor, CTMC
TransTech Pharma Inc.
4170 Mendenhall Oaks Pkwy
High Point, NC 27265
[Back to top]
Molecular Targeting of Protein Kinases to Optimize
Selectivity and Resistance Profiles of Kinase Inhibitors
Jeffrey Jie-Lou Liao
This article reviews several important observations in the
field of protein kinase drug discovery, exemplified mainly
by targeting c-Abl for the treatment of CML. Structure-based
strategy and insight are provided for the optimization of
the selectivity and resistant mutation profiles of protein
kinase inhibitors.
[Back to top]
The Role of Halogen Bonding in Inhibitor Recognition
and Binding by Protein Kinases
Andrea Regier Voth and P. Shing Ho
Halogen bonds are short-range molecular interactions that
are analogous to classical hydrogen bonds, except that a polarized
halogen replaces the hydrogen as the acid in the Lewis acid/base
pair. Such interactions occur regularly in the structures
of many ligand-protein complexes, but have only recently been
recognized in biological systems as a distinct class with
well-defined physical characteristics. In this review, we
survey twelve single crystal structures of protein kinase
complexes with halogenated ligands in order to characterize
the role of halogen bonds in conferring specificity and affinity
for halogenated inhibitors in this important class of enzymes.
From this survey, we attempt to identify the properties of
halogen bonds that can be generally applied to bottom-up strategies
for designing inhibitors for this and other enzyme targets.
[Back to top]
Recent Progress in the Development of ATP-Competitive
and Allosteric Akt Kinase Inhibitors
Craig W. Lindsley, Stanley F. Barnett, Melissa Yaroschak,
Mark T. Bilodeau and Mark E. Layton
This article describes recent advances in the development
and biological evaluation of small molecule inhibitors for
the serine/threonine kinase Akt (PKB). Akt plays a pivotal
role in cell survival and proliferation through a number of
downstream effectors. Recent studies indicate that unregulated
activation of the PI3K/Akt pathway is a prominent feature
of many human cancers and Akt is over-expressed or activated
in all major cancers. Akt is considered an attractive target
for cancer therapy and inhibition of Akt alone or in combination
with standard cancer chemotherapeutics has been postulated
to reduce the apoptotic threshold and preferentially kill
cancer cells. The development of specific and potent inhibitors
will allow this hypothesis to be tested in animals. Recently,
several series of small molecule, ATP-competitive inhibitors
have been reported with a range of Akt potencies and selectivities.
Phosphatidylinositol (PI) analogs have been reported to inhibit
Akt, but these inhibitors may also have specificity problems
with respect to other pleckstrin homology (PH) domain containing
proteins and may have poor bioavailability. In addition, novel
allosteric inhibitors have been reported which are PH domain
dependent, exhibit selectivity for the individual Akt isozymes
and inhibit the activity and the activation of Akt. Compounds
within these classes Akt inhibitors have sufficient potency
and specificity to test for tumor efficacy in animal models
and recently reported preliminary experiments are reviewed.
[Back to top]
Recent Advances of MEK Inhibitors and Their Clinical
Progress
John (Yuan) Wang, Keith M. Wilcoxen, Kenichi Nomoto, and
Sara Wu
The RAS/RAF/MEK/ERK signaling pathway has been a major clinical
focus in oncology research in recent years. A clearer association
of B-RAF mutations to cancers such as melanoma, papillary
thyroid cancer and others has brought an increasing interest
in chemotherapeutics that target this cellular signaling pathway.
In this review, the authors summarize the current understanding
of science and therapeutic use of the MEK inhibitors targeting
the RAS/RAF/ MEK/ERK pathway. Clinical progresses of PD0325901
and AZD6244 are highlighted in addition to developments of
new MEK inhibitors. Recently disclosed MEK inhibitors in two
sub-divided classes, ATP noncompetitive and ATP competitive
inhibitors are discussed.
[Back to top]
Molecular Design and Clinical Development of VEGFR
Kinase Inhibitors
Haizhen Zhong and J. Phillip Bowen
Vascular angiogenesis has been shown to play a key role in
many solid tumors. The vascular endothelial growth factor
(VEGF) isoforms and their tyrosine kinase receptors (VEGFRs)
have been under intense research for effective anticancer
drug candidates. Epidermal growth factor (EGF) and its receptor
(EGFR) provide another pathway critical in monitoring angiogenesis.
VEGF exerts its effect through binding to tyrosine kinase
receptors, mainly VEGFR-1 (Flt-1, the fms-like tyrosine kinase-1)
and VEGFR-2 (Flk-1/KDR, fetal liver kinase-1). This paper
reviews the progress, mechanism, and binding modes of recently
approved kinase inhibitors, such as sunitinib (Sutent®),
sorafenib (Nexavar®)
and dasatinib (Sprycel®),
as well as other inhibitors that are still under clinical
development. Recent clinical treatments suggest that most
inhibitors of VEGFR (and/or EGFR) exert their therapeutic
effect through not only targeting the VEGFR (and/or EGFR)
pathway, but also inhibiting other pathways, such as RAF/MEK/ERK
pathway. A new pharmacophore model for second generation of
type II tyrosine kinase inhibitors and recent advances in
the combination of VEGFR tyrosine kinase inhibitors and other
chemotherapeutics are also covered.
[Back to top]
Targeting Protein Multiple Conformations: A Structure-Based
Strategy for Kinase Drug Design
Jeffrey Jie-Lou Liao and Robert C. Andrews
Multiple conformations of a protein kinase target offer an
opportunity to design small-molecule inhibitors with distinct
but clinically useful profiles. This article analyzes and
classifies the binding pockets in the kinase catalytic cleft
in different conformational states. Targeting kinase multiple
conformations as an emerging strategy in the field is exemplified
with important small-molecule agents in the clinic. The structure-based
analysis in the paper provides a rationale for thwarting the
development of drug-resistant mutations in antikinase therapy.
[Back to top]
A Comparison of Physicochemical Property Profiles
of Marketed Oral Drugs and Orally Bioavailable Anti-Cancer
Protein Kinase Inhibitors in Clinical Development
Adrian L. Gill, Marcel Verdonk, Robert G. Boyle and Richard
Taylor
This manuscript describes a comparison of the physicochemical
properties of marketed oral drugs with those of 45 structurally
confirmed orally bioavailable anti-cancer protein kinase inhibitors
currently in different phases of clinical development. It
is evident from the data presented that these kinase inhibitors
are on average larger (over 110Da), more lipophilic (over
1.5 log units) and more complex (approximately two more rotatable
bonds) than those of marketed oral drugs. In contrast, hydrogen
bond donor (HBD) and hydrogen bond acceptor (HBA) counts are
not significantly different.
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