International Journal of Cancer,
Journal Year:
2010,
Volume and Issue:
129(1), P. 245 - 255
Published: Dec. 17, 2010
Angiogenesis,
a
critical
driver
of
tumor
development,
is
controlled
by
interconnected
signaling
pathways.
Vascular
endothelial
growth
factor
receptor
(VEGFR)
2
and
tyrosine
kinase
with
immunoglobulin
epidermal
homology
domain
play
crucial
roles
in
the
biology
normal
vasculature.
Regorafenib
(BAY
73-4506),
novel
oral
multikinase
inhibitor,
potently
inhibits
these
cell
kinases
biochemical
cellular
phosphorylation
assays.
Furthermore,
regorafenib
additional
angiogenic
(VEGFR1/3,
platelet-derived
receptor-β
fibroblast
1)
mutant
oncogenic
KIT,
RET
B-RAF.
The
antiangiogenic
effect
was
demonstrated
vivo
dynamic
contrast-enhanced
magnetic
resonance
imaging.
administered
once
orally
at
10
mg/kg
significantly
decreased
extravasation
Gadomer
vasculature
rat
GS9L
glioblastoma
xenografts.
In
daily
(qd)×4
dosing
study,
pharmacodynamic
effects
persisted
for
48
hr
after
last
correlated
inhibition
(TGI).
A
significant
reduction
microvessel
area
observed
human
colorectal
xenograft
qd×5
30
mg/kg.
exhibited
potent
dose-dependent
TGI
various
preclinical
models
mice,
shrinkages
breast
MDA-MB-231
renal
786-O
carcinoma
models.
Pharmacodynamic
analyses
model
revealed
strong
staining
proliferation
marker
Ki-67
phosphorylated
extracellular
regulated
1/2.
These
data
demonstrate
that
well-tolerated,
active
inhibitor
distinct
target
profile
may
have
therapeutic
benefit
malignancies.
Molecular Cancer,
Journal Year:
2018,
Volume and Issue:
17(1)
Published: Feb. 15, 2018
The
human
genome
encodes
538
protein
kinases
that
transfer
a
γ-phosphate
group
from
ATP
to
serine,
threonine,
or
tyrosine
residues.
Many
of
these
are
associated
with
cancer
initiation
and
progression.
recent
development
small-molecule
kinase
inhibitors
for
the
treatment
diverse
types
has
proven
successful
in
clinical
therapy.
Significantly,
second
most
targeted
drug
targets,
after
G-protein-coupled
receptors.
Since
first
inhibitor,
early
1980s,
37
have
received
FDA
approval
malignancies
such
as
breast
lung
cancer.
Furthermore,
about
150
kinase-targeted
drugs
phase
trials,
many
kinase-specific
preclinical
stage
development.
Nevertheless,
factors
confound
efficacy
molecules.
Specific
tumor
genetics,
microenvironment,
resistance,
pharmacogenomics
determine
how
useful
compound
will
be
given
This
review
provides
an
overview
discovery
relation
oncology
highlights
challenges
future
potential
therapies.
Angewandte Chemie International Edition,
Journal Year:
2015,
Volume and Issue:
54(11), P. 3290 - 3327
Published: Jan. 28, 2015
Abstract
Structure‐based
ligand
design
in
medicinal
chemistry
and
crop
protection
relies
on
the
identification
quantification
of
weak
noncovalent
interactions
understanding
role
water.
Small‐molecule
protein
structural
database
searches
are
important
tools
to
retrieve
existing
knowledge.
Thermodynamic
profiling,
combined
with
X‐ray
computational
studies,
is
key
elucidate
energetics
replacement
water
by
ligands.
Biological
receptor
sites
vary
greatly
shape,
conformational
dynamics,
polarity,
require
different
ligand‐design
strategies,
as
shown
for
various
case
studies.
Interactions
between
dipoles
have
become
a
central
theme
molecular
recognition.
Orthogonal
interactions,
halogen
bonding,
amide⋅⋅⋅π
stacking
provide
new
innovative
lead
optimization.
The
combination
synthetic
models
biological
complexation
studies
required
gather
reliable
information
