| Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 7, Number 6, November 2007
Contents
Non-Receptor Tyrosine Kinases as Molecular Targets
for Patient Tailored Cancer Therapy
Guest Editors: F.M. Uckun, A. Vassilev and H.
Tibbles
Editorial Pp. 593
Oncogenic Fusion Tyrosine Kinases as Molecular Targets
for Anti-Cancer Therapy Pp. 594-611
R.H. Gunby, E. Sala, C.J. Tartari, M. Puttini, C. Gambacorti
Passerini and L. Mologni
[Abstract]
Targeting JAK3 Tyrosine Kinase-Linked Signal Transduction
Pathways with Rationally-Designed Inhibitors Pp.
612-623
F.M. Uckun, A. Vassilev, I. Dibirdik and H. Tibbles
[Abstract]
Bruton’s Tyrosine Kinase as a New Therapeutic
Target Pp. 624-632
F.M. Uckun, H.E. Tibbles and A.O. Vassilev
[Abstract]
Non-Receptor Tyrosine Kinase Inhibitors in Lung Cancer
Pp. 633-642
O. Hahn and R. Salgia
[Abstract]
Jak2 Tyrosine Kinase and Cancer: How Good Cells Get
HiJAKed Pp. 643-650
M.D. Godeny and P.P. Sayeski
[Abstract]
Src Family Nonreceptor Tyrosine Kinases as Molecular
Targets for Cancer Therapy Pp. 651-659
F.M. Johnson and G.E. Gallick
[Abstract]
Synthetic Src-Kinase Domain Inhibitors and Their Structural
Requirements Pp. 660-680
S. Schenone, F. Manetti and M. Botta
[Abstract]
Role of Focal Adhesion Kinase in Human Cancer: A Potential
Target for Drug Discovery Pp. 681-684
E.K.-H. Han and T. McGonigal
[Abstract]
General Article
Synthesis and Structure-Activity Relationships of Potent Antitumor
Active Quinoline and Naphthyridine Derivatives Pp.
685-709
S.K. Srivastava, A. Jha, S.K. Agarwal, R. Mukherjee and
A.C. Burman
[Abstract]
Abstracts
[Back to top]
Editorial
Protein tyrosine kinases (PTKs) play important roles in biochemical
signaling events related to cellular activation, differentiation,
proliferation, and survival. Because of their contribution
to chemotherapy resistance as well as growth of human cancers,
several PTKs have emerged as new molecular targets in cancer
therapy. The reported clinical successes with the anti-HER2
monoclonal antibody Herceptin in breast cancer, anti-EGFRI
antibody Erbitux in colon cancer, and small molecule kinase
inhibitor Gleevec in BCR-ABL positive leukemias have resulted
in a paradigm-shift in treatment of cancer and sparked interest
in tyrosine kinase inhibitors as a new class of promising
drug candidates.
In this issue, we explore the clinical potential of small
molecule inhibitors targeting the JAK, SRC, TEC and FAK family
of PTK. Many of these drug candidates in the PTK inhibitor
pipeline have entered into clinical testing, while others
are at advanced preclinical stages. Our issue begins with
an overview by Gunby et al. entitled “Oncogenic
fusion tyrosine kinases as molecular targets for anti-cancer
therapy”. In two of the review articles, the potential
of rationally designed selective tyrosine kinase inhibitors
targeting JAK3 and BTK are discussed by Uckun, Vassilev, and
Tibbles. In the article entitled “Non-Receptor Tyrosine
Kinase Inhibitors in Lung Cancer”, Hahn and Salgia discuss
the development of tyrosine kinase inhibitors for lung cancer.
Godeny and Sayeski review the role of Janus Kinase 2 (Jak2)
in both classical cellular signaling and neoplastic growth
in “Jak2 Tyrosine Kinase and Cancer: How Good Cells
Get HiJAKed”. In their article entitled “Src Family
of Non-Receptor Tyrosine Kinases as Molecular Targets for
Cancer Therapy”, Johnson and Gallick discuss the potential
of SRC kinase inhibitors.
Schenone, Manetti and Botta continue the discussion of SRC
kinase inhibitors in their article “Synthetic Src-kinase
domain inhibitors and their structural requirements”.
Finally, in the review entitled “Role of Focal Adhesion
Kinase in Human Cancer: A Potential Target for Drug Discovery”,
Han and McGonigal discuss FAK kinase inhibitors.
We are hopeful that these review articles will serve as a
useful reference and guide for readers who are interested
in learning more about the role of PTK in cancer biology and
the clinical potential of PTK inhibitors.
Fatih M. Uckun, M.D.
Parker Hughes Cancer Center
Alexei Vassilev, Ph.D.
Paradigm Pharmaceuticals
Heather Tibbles, B.S.
Parker Hughes Institute
[Back to top]
Oncogenic Fusion Tyrosine Kinases as Molecular Targets
for Anti-Cancer Therapy
R.H. Gunby, E. Sala, C.J. Tartari, M. Puttini, C. Gambacorti
Passerini and L. Mologni
Deregulated activation of protein tyrosine kinases (PTKs)
is a frequent event underlying malignant transformation in
many types of cancer. The formation of oncogenic fusion tyrosine
kinases (FTKs) resulting from genomic rearrangements, represents
a common mechanism by which kinases escape the strict controls
that normally regulate their expression and activation. FTKs
are typically composed of an N-terminal dimerisation domain,
provided by the fusion partner protein, fused to the kinase
domain of receptor or non-receptor tyrosine kinases (non-RTKs).
Since FTKs do not contain extracellular domains, they share
many characteristics with non-RTKs in terms of their properties
and approaches for therapeutic targeting. FTKs are cytoplasmic
or sometimes nuclear proteins, depending on the normal distribution
of their fusion partner. FTKs no longer respond to ligand
and are instead constitutively activated by dimerisation induced
by the fusion partner. Unlike RTKs, FTKs cannot be targeted
by therapeutic antibodies, instead they require agents that
can cross the cell membrane as with non-RTKs. Here we review
the PTKs known to be expressed as FTKs in cancer and the strategies
for molecularly targeting these FTKs in anti-cancer therapy.
[Back to top]
Targeting JAK3 Tyrosine Kinase-Linked Signal Transduction
Pathways with Rationally-Designed Inhibitors
F.M. Uckun, A. Vassilev, I. Dibirdik and H. Tibbles
Inhibitors of Janus Kinase 3 (JAK3) show potential as a new
class of apoptosis-inducing anti-cancer drugs. In addition,
JAK3 inhibitors may also be useful as immunosuppressive agents.
Rationally designed selective inhibitors of JAK3 such as JANEX-1,
that do not inhibit other Janus kinases have recently undergone
extensive preclinical testing that revealed a favorable pharmacodynamic
profile. Here we discuss the clinical potential of targeting
JAK3-linked signal transduction pathways with small molecule
inhibitors such as JANEX-1.
[Back to top]
Bruton’s Tyrosine Kinase as a New Therapeutic
Target
F.M. Uckun, H.E. Tibbles and A.O. Vassilev
Targeting Bruton’s tyrosine kinase (BTK) with a small
molecule inhibitor may be useful in treatment of BTK-expressing
malignancies because of the anti-apoptotic function of BTK
in cancer cells. Furthermore, BTK inhibitors also exhibit
anti-thrombotic properties that may be desirable in the context
of the increased risk of thromboembolic complications in cancer
patients. This review will focus on the role of BTK in drug
resistance in cancer, thromboembolism, and various pathologic
immune responses, such as graft versus host disease. The therapeutic
potential of targeting BTK is illustrated by discussion of
the biologic activity profile of the rationally designed BTK
inhibitor LFM-A13.
[Back to top]
Non-Receptor Tyrosine Kinase Inhibitors in Lung Cancer
O. Hahn and R. Salgia
Lung cancer is a leading cause of cancer death. Systemic therapies
with cytotoxic chemotherapies remain ineffective. Current
research efforts in lung cancer have focused on developing
novel agents to target cellular pathways that are altered
in lung cancer. Protein tyrosine kinases are a family of oncogenes
that regulate important cellular processes such as differentiation,
proliferation, cell cycle, motility, and apoptosis. In this
article, we review non receptor tyrosine kinases’ role
in lung cancer and the development of agents that target these
proteins.
[Back to top]
Jak2 Tyrosine Kinase and Cancer: How Good Cells Get
HiJAKed
M.D. Godeny and P.P. Sayeski
Cloned in 1992, Jak2 tyrosine kinase has emerged as a critical
molecule in mammalian development, physiology, and disease.
Here, we will review the early history of Jak2 as it pertains
to its role in classical cellular signaling. We also review
how specific structural determinants within Jak2 dictate its
overall function. Finally, we will review relatively recent
literature as it pertains to the role of Jak2 in neoplastic
growth as well as the identification of novel Jak2 inhibitors.
It is our hope that by reviewing these specific areas, we
will have a better understanding of the role of Jak2 in cancer,
and in turn, we may have a better idea as to how to block
aberrant Jak2 function.
[Back to top]
Src Family Nonreceptor Tyrosine Kinases as Molecular
Targets for Cancer Therapy
F.M. Johnson and G.E. Gallick
The Src family of kinases has nine known members, all of which
are nonreceptor tyrosine kinases involved in signal transduction
in both normal and cancer cells. Interest in these kinases
has increased recently because of the development, initial
clinical success, and low toxicity of pharmacologic inhibitors.
c-Src is the best-studied member of the Src family and the
one most often implicated in cancer progression. c-Src has
multiple substrates that lead to diverse biologic effects,
including changes in proliferation, motility, invasion, survival,
and angiogenesis. c-Src has been most extensively studied
in colon cancer where correlative and direct experimental
evidence has shown that it mediates several aspects of cancer
cell progression. c-Src has a similar role in multiple tumor
types, including pancreatic cancer, breast cancer, lung cancer,
head and neck squamous cell carcinoma, and prostate cancer.
Several inhibitors of the Src family kinases are in clinical
development; three are currently being studied in clinical
trials. Initial data from these trials suggest that these
agents are well tolerated. Future clinical development of
these inhibitors will include trials in patients with solid
tumors and of combination therapy.
[Back to top]
Synthetic Src-Kinase Domain Inhibitors and Their Structural
Requirements
S. Schenone, F. Manetti and M. Botta
Protein tyrosine kinases catalyze the transfer of phosphoryl
groups from ATP to amino acids on proteins and play a fundamental
role in signal transduction pathways in mammalian cells. In
particular, Src and Src-family are non-receptor tyrosine kinases
that regulate cell growth, differentiation, migration, adhesion
and apoptosis. Src-family members share common features, with
well defined domains. The activation of these enzymes in response
to a variety of stimuli leads from a close and inactive conformation
to an open and active one, through a balance of phosphorylation
and dephosphorylation of the enzyme structure, characterized
in different cases by X-ray crystallography. Overexpression,
deregulation or mutations of these enzymes have been observed
and studied in many diseases, first of all in many human malignancies,
such as colon, breast, pancreatic and other cancers. Src-family
is also involved in other pathologic situations, such as osteoporosis,
cardiovascular diseases, immune system disorders, and, recently,
it has been also demonstrated the involvement of Src in prion
diseases.Therefore, Src-family is an attractive and fundamental
target for the design of new therapeutic agents against different
pathologies, in particular cancer and bone diseases. Currently,
there is no approved drug acting as Src kinase inhibitor,
but new molecules, very potent and selective toward this family
of kinases and also in vivo, are continuously synthesized,
as demonstrated by the high number of publications and patents
in this field. Here, we report several examples of Src kinase
domain inhibitors, focusing our attention on chemical structures,
structure-activity relationships and mechanism of action.
[Back to top]
Role of Focal Adhesion Kinase in Human Cancer: A Potential
Target for Drug Discovery
E.K.-H. Han and T. McGonigal
The focal adhesion kinase (FAK) is a non-receptor tyrosine
kinase that localizes to the points of cell contact with the
extracellular matrix, called focal adhesions. FAK is involved
in several cellular processes including invasion, motility,
proliferation and apoptosis. In in vivo animal studies,
FAK has been shown to contribute to tumor development and
malignancy. Furthermore, FAK expression was shown to be elevated
in a number of human cancers. Increased FAK expression and
activity are correlated with malignant phenotype and poor
prognosis in patients. Taken together, these studies suggest
that FAK is a potentially good target for drug discovery.
In this review, FAK and its relationship to cancer, as well
as approaches to therapeutic intervention of FAK will be discussed.
[Back to top]
Synthesis and Structure-Activity Relationships of Potent Antitumor
Active Quinoline and Naphthyridine Derivatives
S.K. Srivastava, A. Jha, S.K. Agarwal, R. Mukherjee and
A.C. Burman
The disease of cancer has been ranked second after cardiovascular
diseases and plant-derived molecules have played an important
role for the treatment of cancer. Nine cytotoxic plant-derived
molecules such as vinblastine, vincristine, navelbine, etoposide,
teniposide, taxol, taxotere, topotecan and irinotecan have
been approved as anticancer drugs. Recently, epothilones are
being emerging as future potential anti-tumor agents. However,
targeted cancer therapy has now been rapidly expanding and
small organic molecules are being exploited for this purpose.
Amongst target specific small organic molecules, quinazoline
was found as one of the most successful chemical class in
cancer chemotherapy as three drugs namely Gefitinib, Erlotinib
and Canertinib belong to this series. Now, quinazoline related
chemical classes such as quinolines and naphthyridines are
being exploited in cancer chemotherapy and a number of molecules
such as compounds EKB-569 (52), HKI-272 (78) and SNS-595 (127a)
are in different phases of clinical trials. This review presents
the synthesis of quinolines and naphthyridines derivatives,
screened for anticancer activity since year 2000. The synthesis
of most potent derivatives in each prototype has been delineated.
A brief structure activity relationship for each prototype
has also been discussed. It has been observed that aniline
group at C-4, aminoacrylamide substituents at C-6, cyano group
at C-3 and alkoxy groups at C-7 in the quinoline ring play
an important role for optimal activity. While aminopyrrolidine
functionality at C-7, 2’-thiazolyl at N-1 and carboxy
group at C-3 in 1,8-naphthyridine ring are essential for eliciting
the cytotoxicity. This review would help the medicinal chemist
to design and synthesize molecules for targeted cancer chemotherapy.
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