The
p27
protein
is
a
canonical
negative
regulator
of
cell
proliferation
and
acts
primarily
by
inhibiting
cyclin-dependent
kinases
(CDKs).
Under
some
circumstances,
associated
with
active
CDK4,
but
no
mechanism
for
activation
has
been
described.
We
found
that
p27,
when
phosphorylated
tyrosine
kinases,
allosterically
activated
CDK4
in
complex
cyclin
D1
(CDK4-CycD1).
Structural
biochemical
data
revealed
binding
(phosp27)
to
altered
the
kinase
adenosine
triphosphate
site
promote
phosphorylation
retinoblastoma
tumor
suppressor
(Rb)
other
substrates.
Surprisingly,
purified
endogenous
phosp27-CDK4-CycD1
complexes
were
insensitive
CDK4-targeting
drug
palbociclib.
Palbociclib
instead
targeted
monomeric
CDK6
(CDK4/6)
breast
cells.
Our
characterize
as
an
Rb
refractory
clinically
relevant
CDK4/6
inhibitors.
Cancer Discovery,
Год журнала:
2020,
Номер
10(3), С. 351 - 370
Опубликована: Фев. 18, 2020
Drugs
targeting
the
cell
cycle-regulatory
cyclin-dependent
kinase
(CDK)
4
and
6
have
been
approved
for
treatment
of
hormone
receptor-positive
breast
cancer,
inhibitors
other
cell-cycle
CDKs
are
currently
in
clinical
trials.
Another
class
CDKs,
transcription-associated
including
CDK7,
CDK8,
CDK9,
CDK12
CDK13,
critical
regulators
gene
expression.
Recent
evidence
suggests
several
novel
functions
these
regulation
epigenetic
modifications,
intronic
polyadenylation,
DNA-damage
responses,
genomic
stability.
Here,
we
summarize
our
current
understanding
transcriptional
their
utility
as
biomarkers,
potential
therapeutic
targets.
SIGNIFICANCE:
CDK
CDK4
CDK6
Several
studies
now
point
to
opportunities
by
inhibiting
well
vulnerabilities
with
PARP
immunotherapy
tumors
deficient
CDKs.
Journal of Clinical and Experimental Hepatology,
Год журнала:
2019,
Номер
9(2), С. 221 - 232
Опубликована: Янв. 27, 2019
Hepatocellular
carcinoma
(HCC)
is
swiftly
increasing
in
prevalence
globally
with
a
high
mortality
rate.
The
progression
of
HCC
patients
induced
advanced
fibrosis,
mainly
cirrhosis,
and
hepatitis.
absence
proper
preventive
or
curative
treatment
methods
encouraged
extensive
research
against
to
develop
new
therapeutic
strategies.
Food
Drug
Administration-approved
Nexavar
(sorafenib)
used
the
unresectable
HCC.
In
2017,
Stivarga
(regorafenib)
Opdivo
(nivolumab)
got
approved
for
after
being
treated
sorafenib,
2018,
Lenvima
(lenvatinib)
But,
owing
rapid
drug
resistance
development
toxicities,
these
options
are
not
completely
satisfactory.
Therefore,
there
an
urgent
need
systemic
combination
therapies
that
target
different
signaling
mechanisms,
thereby
decreasing
prospect
cancer
cells
developing
treatment.
this
review,
etiology
strategies
include
currently
drugs
other
potential
candidates
such
as
Milciclib,
palbociclib,
galunisertib,
ipafricept,
ramucirumab
evaluated.
Since
their
characterization
as
conserved
modules
that
regulate
progression
through
the
eukaryotic
cell
cycle,
cyclin-dependent
protein
kinases
(CDKs)
in
higher
cells
are
now
also
emerging
significant
regulators
of
transcription,
metabolism
and
differentiation.
The
cyclins,
though
originally
characterized
CDK
partners,
have
CDK-independent
roles
include
regulation
DNA
damage
repair
transcriptional
programmes
direct
differentiation,
apoptosis
metabolic
flux.
This
review
compares
structures
members
cyclin
families
determined
by
X-ray
crystallography,
considers
what
mechanistic
insights
they
provide
to
guide
functional
studies
distinguish
CDK-
cyclin-specific
activities.
Aberrant
activity
is
a
hallmark
number
diseases,
structural
can
important
identify
novel
routes
therapy.
Journal of Medicinal Chemistry,
Год журнала:
2018,
Номер
62(9), С. 4233 - 4251
Опубликована: Дек. 13, 2018
Cyclin-dependent
kinase
2
(CDK2)
drives
the
progression
of
cells
into
S-
and
M-phases
cell
cycle.
CDK2
activity
is
largely
dispensable
for
normal
development,
but
it
critically
associated
with
tumor
growth
in
multiple
cancer
types.
Although
role
tumorigenesis
has
been
controversial,
emerging
evidence
proposes
that
selective
inhibition
may
provide
a
therapeutic
benefit
against
certain
tumors,
continues
to
appeal
as
strategy
exploit
anticancer
drug
development.
Several
small-molecule
inhibitors
have
progressed
clinical
trials.
However,
CDK2-selective
inhibitor
yet
be
discovered.
Here,
we
discuss
latest
understandings
cells,
review
core
pharmacophores
used
target
CDK2,
outline
strategies
rational
design
inhibitors.
We
attempt
an
outlook
on
how
open
new
avenues
therapy.
