Journal of Virology,
Journal Year:
2023,
Volume and Issue:
97(9)
Published: Sept. 6, 2023
Latent
HIV-1
provirus
represents
the
barrier
toward
a
cure
for
infection
and
is
dependent
upon
host
RNA
Polymerase
(Pol)
II
machinery
reemergence.
Here,
we
find
that
inhibitors
of
Pol
mediator
kinases
CDK8/19,
Senexin
A
BRD6989,
inhibit
induction
expression
in
response
to
latency-reversing
agents
T
cell
signaling
agonists.
These
were
found
impair
recruitment
LTR.
Furthermore,
several
latency
reversal
was
impaired
disruption
CDK8
by
shRNA
or
gene
knockout.
However,
effects
depletion
did
not
entirely
mimic
CDK8/19
kinase
inhibition
suggesting
are
functionally
redundant.
Additionally,
treatment
CD4+
peripheral
blood
mononuclear
cells
isolated
from
people
living
with
who
receiving
antiretroviral
therapy
inhibited
viral
replication
stimulation
PMA
ionomycin.
observations
indicate
kinases,
CDK19,
play
significant
role
regulation
transcription
small
molecule
these
enzymes
may
contribute
therapies
designed
promote
deep
involving
durable
suppression
expression.
IMPORTANCE
will
require
novel
can
force
elimination
contain
copies
virus
genome
inserted
into
chromosome,
but
which
shut
off,
silenced.
known
as
latently-infected
cells,
represent
main
reason
why
current
HIV/AIDS
cannot
because
unaffected
drugs.
Our
results
chemical
Cdk8
also
latent
HIV
provirus.
an
important
enzyme
regulates
genes
signals
need
respond
produced
frequently
mutated
cancers.
be
employed
prevent
provirus,
might
eventually
enable
infected
individuals
cease
Endocrine Reviews,
Journal Year:
2021,
Volume and Issue:
43(4), P. 678 - 719
Published: Nov. 6, 2021
Abstract
Uterine
fibroids
are
benign
monoclonal
neoplasms
of
the
myometrium,
representing
most
common
tumors
in
women
worldwide.
To
date,
no
long-term
or
noninvasive
treatment
option
exists
for
hormone-dependent
uterine
fibroids,
due
to
limited
knowledge
about
molecular
mechanisms
underlying
initiation
and
development
fibroids.
This
paper
comprehensively
summarizes
recent
research
advances
on
focusing
risk
factors,
origin,
pathogenetic
mechanisms,
options.
Additionally,
we
describe
current
interventions
Finally,
future
perspectives
studies
summarized.
Deeper
mechanistic
insights
into
tumor
etiology
complexity
can
contribute
progress
newer
targeted
therapies.
Genes & Development,
Journal Year:
2020,
Volume and Issue:
34(7-8), P. 465 - 488
Published: April 1, 2020
RNA
polymerase
II
(Pol
II)
transcribes
all
protein-coding
genes
and
many
noncoding
RNAs
in
eukaryotic
genomes.
Although
Pol
is
a
complex,
12-subunit
enzyme,
it
lacks
the
ability
to
initiate
transcription
cannot
consistently
transcribe
through
long
DNA
sequences.
To
execute
these
essential
functions,
an
array
of
proteins
protein
complexes
interact
with
regulate
its
activity.
In
this
review,
we
detail
structure
mechanism
over
dozen
factors
that
govern
initiation
(e.g.,
TFIID,
TFIIH,
Mediator),
pausing,
elongation
DSIF,
NELF,
PAF,
P-TEFb).
The
structural
basis
for
regulation
has
advanced
rapidly
past
decade,
largely
due
technological
innovations
cryoelectron
microscopy.
Here,
summarize
wealth
functional
data
have
enabled
deeper
understanding
mechanisms;
also
highlight
mechanistic
questions
remain
unanswered
or
controversial.
Cancer Discovery,
Journal Year:
2020,
Volume and Issue:
10(3), P. 351 - 370
Published: Feb. 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.
Signal Transduction and Targeted Therapy,
Journal Year:
2025,
Volume and Issue:
10(1)
Published: Jan. 12, 2025
Abstract
Cyclin
Dependent
Kinases
(CDKs)
are
closely
connected
to
the
regulation
of
cell
cycle
progression,
having
been
first
identified
as
kinases
able
drive
division.
In
reality,
human
genome
contains
20
different
CDKs,
which
can
be
divided
in
at
least
three
sub-family
with
functions,
mechanisms
regulation,
expression
patterns
and
subcellular
localization.
Most
these
play
fundamental
roles
normal
physiology
eucaryotic
cells;
therefore,
their
deregulation
is
associated
onset
and/or
progression
multiple
disease
including
but
not
limited
neoplastic
neurodegenerative
conditions.
Here,
we
describe
functions
categorized
into
main
functional
groups
they
classified,
highlighting
most
relevant
pathways
that
functions.
We
then
discuss
potential
CDKs
pathologies,
a
particular
focus
on
cancer,
have
extensively
studied
explored
therapeutic
targets.
Finally,
how
inhibitors
become
standard
therapies
selected
cancers
propose
novel
ways
investigation
export
targeting
from
cancer
other
chronic
diseases.
hope
effort
made
collecting
all
available
information
both
prominent
lesser-known
CDK
family
members
will
help
identify
develop
areas
research
improve
lives
patients
affected
by
debilitating
Retrovirology,
Journal Year:
2024,
Volume and Issue:
21(1)
Published: April 5, 2024
Abstract
Transcriptionally
latent
forms
of
replication-competent
proviruses,
present
primarily
in
a
small
subset
memory
CD4
+
T
cells,
pose
the
primary
barrier
to
cure
for
HIV-1
infection
because
they
are
source
viral
rebound
that
almost
inevitably
follows
interruption
antiretroviral
therapy.
Over
last
30
years,
many
factors
essential
initiating
transcription
have
been
identified
studies
performed
using
transformed
cell
lines,
such
as
Jurkat
T-cell
model.
However,
highlighted
this
review,
several
poorly
understood
mechanisms
still
need
be
elucidated,
including
molecular
basis
promoter-proximal
pausing
transcribing
complex
and
detailed
mechanism
delivery
P-TEFb
from
7SK
snRNP.
Furthermore,
central
paradox
remains
unsolved:
how
initial
rounds
achieved
absence
Tat?
A
critical
limitation
models
is
do
not
recapitulate
transitions
between
active
effector
cells
quiescent
cells.
Therefore,
investigation
latency
reversal
LRA
efficacy
proper
physiological
context
requires
utilization
models.
Recent
mechanistic
latently
infected
recovered
donors
ex
vivo
cellular
demonstrated
blocks
restrictive
epigenetic
features
at
proviral
promoter,
cytoplasmic
sequestration
key
initiation
NFAT
NF-κB,
vanishingly
low
expression
elongation
factor
P-TEFb.
One
foremost
schemes
eliminate
residual
reservoir
deliberately
reactivate
proviruses
enable
clearance
persisting
cells—the
“Shock
Kill”
strategy.
For
become
efficient,
effective,
non-toxic
latency-reversing
agents
(LRAs)
must
discovered.
Since
multiple
restrictions
limit
reactivation
understanding
signaling
stimulating
biogenesis,
activation,
reversing
prerequisite
development
more
effective
LRAs.
Journal of Medicinal Chemistry,
Journal Year:
2020,
Volume and Issue:
63(22), P. 13228 - 13257
Published: Aug. 31, 2020
Cyclin-dependent
kinase
9
(CDK9),
which
regulates
transcriptional
elongation,
is
an
attractive
therapeutic
target
for
many
cancers,
especially
cancers
driven
by
dysregulation.
In
particular,
CDK9
promotes
RNA
polymerase
II
pause/release,
a
rate-limiting
step
in
normal
regulation
that
frequently
dysregulated
cancers.
Emerging
evidence
indicates
selective
inhibition
or
degradation
may
provide
benefit
against
certain
Indeed,
the
development
of
modulators
(inhibitors
and
degraders)
has
attracted
great
attention,
with
several
molecules
currently
under
clinical
development.
This
review
provides
overview
recent
advances
general,
special
emphasis
on
compounds
evaluation
new
emerging
strategies,
such
as
proteolysis
targeting
chimeras
(PROTACs).
Journal of Medicinal Chemistry,
Journal Year:
2022,
Volume and Issue:
65(9), P. 6390 - 6418
Published: April 29, 2022
Herein,
we
discuss
more
than
50
cyclin-dependent
kinase
(CDK)
inhibitors
that
have
been
approved
or
undergone
clinical
trials
and
their
therapeutic
application
in
multiple
cancers.
This
review
discusses
the
design
strategies,
structure–activity
relationships,
efficacy
performances
of
these
selective
nonselective
CDK
inhibitors.
The
theoretical
basis
early
broad-spectrum
is
similar
to
scope
chemotherapy,
but
because
toxicity
greater
benefit,
there
no
window.
notion
a
safer
potential
pan-CDK
has
widely
recognized
during
research
process.
Four
CDK4/6
for
treatment
breast
cancer
prophylactic
administration
chemotherapy
protect
bone
marrow
immune
system
function.
Furthermore,
emerging
strategies
field
are
summarized
briefly,
CDKs
continue
be
pursued
as
anticancer
drug
targets
discovery.