Journal of Medicinal Chemistry,
Journal Year:
2021,
Volume and Issue:
64(24), P. 18025 - 18053
Published: Dec. 15, 2021
Bromodomain-containing
protein
4
(BRD4)
is
an
attractive
epigenetic
target
in
human
cancers.
Inhibiting
the
phosphorylation
of
BRD4
by
casein
kinase
2
(CK2)
a
potential
strategy
to
overcome
drug
resistance
cancer
therapy.
The
present
study
describes
synthesis
multiple
BRD4–CK2
dual
inhibitors
based
on
rational
design,
structure–activity
relationship,
and
vitro
vivo
evaluations,
44e
was
identified
possess
potent
balanced
activities
against
(IC50
=
180
nM)
CK2
230
nM).
In
experiments
show
that
could
inhibit
proliferation
induce
apoptosis
autophagy-associated
cell
death
MDA-MB-231
MDA-MB-468
cells.
two
xenograft
mouse
models,
displays
anticancer
activity
without
obvious
toxicities.
Taken
together,
we
successfully
synthesized
first
highly
effective
inhibitor,
which
expected
be
therapeutic
for
triple-negative
breast
(TNBC).
Journal of Medicinal Chemistry,
Journal Year:
2022,
Volume and Issue:
65(19), P. 13029 - 13040
Published: Sept. 28, 2022
Proteolysis-targeting
chimeras
(PROTACs)
must
be
cell
permeable
to
reach
their
target
proteins.
This
is
challenging
as
the
bivalent
structure
of
PROTACs
puts
them
in
chemical
space
at,
or
beyond,
outer
limits
oral
druggable
space.
We
used
NMR
spectroscopy
and
molecular
dynamics
(MD)
simulations
independently
gain
insights
into
origin
differences
permeability
displayed
by
three
flexible
cereblon
having
closely
related
structures.
Both
methods
revealed
that
propensity
adopt
folded
conformations
with
a
low
solvent-accessible
3D
polar
surface
area
an
apolar
environment
correlated
high
permeability.
The
nature
flexibility
linker
were
essential
for
populate
stabilized
intramolecular
hydrogen
bonds,
π–π
interactions,
van
der
Waals
interactions.
conclude
MD
may
prospective
ranking
design
PROTACs.
Journal of Medicinal Chemistry,
Journal Year:
2022,
Volume and Issue:
65(15), P. 10133 - 10160
Published: July 25, 2022
Polo-like
kinase
1
(PLK1)
plays
an
important
role
in
a
variety
of
cellular
functions,
including
the
regulation
mitosis,
DNA
replication,
autophagy,
and
epithelial–mesenchymal
transition
(EMT).
PLK1
overexpression
is
often
associated
with
cell
proliferation
poor
prognosis
cancer
patients,
making
it
promising
antitumor
target.
To
date,
at
least
10
inhibitors
(PLK1i)
have
been
entered
into
clinical
trials,
among
which
typical
domain
(KD)
inhibitor
BI
6727
(volasertib)
was
granted
"breakthrough
therapy
designation"
by
FDA
2013.
Unfortunately,
many
other
KD
showed
specificity,
resulting
dose-limiting
toxicity,
has
greatly
impeded
their
development.
Researchers
recently
discovered
PLK1i
higher
selectivity,
stronger
potency,
better
absorption,
distribution,
metabolism,
elimination
(ADME)
characteristics.
In
this
review,
we
emphasize
structure–activity
relationships
(SARs)
PLK1i,
providing
insights
new
drugs
targeting
for
practice.
Cell Death and Disease,
Journal Year:
2022,
Volume and Issue:
13(12)
Published: Dec. 20, 2022
Abstract
Epigenetic
factor
Brd4
has
emerged
as
a
key
regulator
of
cancer
cell
proliferation.
Targeted
inhibition
suppresses
growth
and
induces
apoptosis
various
cells.
In
addition
to
apoptosis,
also
been
shown
regulate
several
other
forms
programmed
death
(PCD),
including
autophagy,
necroptosis,
pyroptosis,
ferroptosis,
with
different
biological
outcomes.
PCD
plays
roles
in
development
tissue
homeostasis
by
eliminating
unnecessary
or
detrimental
Dysregulation
is
associated
human
diseases,
cancer,
neurodegenerative
infectious
diseases.
this
review,
we
discussed
some
recent
findings
on
how
actively
regulates
the
therapeutic
potentials
targeting
PCD-related
A
better
understanding
regulation
would
provide
not
only
new
insights
into
pathophysiological
functions
but
avenues
for
therapy
Brd4-regulated
PCD.
BioEssays,
Journal Year:
2021,
Volume and Issue:
43(12)
Published: Oct. 26, 2021
Bromodomain-containing
4
(BRD4),
a
member
of
Bromo
and
Extra-Terminal
(BET)
family,
recognizes
acetylated
histones
is
importance
in
transcription,
replication,
DNA
repair.
It
also
binds
non-histone
proteins,
RNA,
contributing
to
development,
tissue
growth,
various
physiological
processes.
Additionally,
BRD4
has
been
implicated
driving
diverse
diseases,
ranging
from
cancer,
viral
infection,
inflammation
neurological
disorders.
Inhibiting
its
functions
with
BET
inhibitors
(BETis)
suppresses
the
progression
several
types
creating
an
impetus
for
translating
these
chemicals
clinic.
The
roles
are
largely
dependent
on
interaction
partners
different
contexts.
In
this
review
we
discuss
molecular
mechanisms
interacting
physiology
pathology.
Current
development
BETis
summarized.
Further
understanding
will
facilitate
resolving
liabilities
present
accelerate
their
clinical
translation.
Medicinal Research Reviews,
Journal Year:
2021,
Volume and Issue:
42(2), P. 710 - 743
Published: Oct. 11, 2021
Abstract
Bromodomain‐containing
protein
4
(BRD4),
as
the
most
studied
member
of
bromodomain
and
extra‐terminal
(BET)
family,
is
a
chromatin
reader
interpreting
epigenetic
codes
through
binding
to
acetylated
histones
non‐histone
proteins,
thereby
regulating
diverse
cellular
processes
including
cell
cycle,
differentiation,
proliferation.
As
promising
drug
target,
BRD4
function
closely
related
cancer,
inflammation,
cardiovascular
disease,
liver
fibrosis.
Currently,
clinical
resistance
BET
inhibitors
has
limited
their
applications
but
synergistic
antitumor
effects
have
been
observed
when
used
in
combination
with
other
tumor
targeting
additional
components
such
PLK1,
HDAC,
CDK,
PARP1.
Therefore,
designing
dual‐target
bromodomains
rational
strategy
cancer
treatment
increase
potency
reduce
resistance.
This
review
summarizes
structures
biological
functions
discusses
recent
advances
dual
from
medicinal
chemistry
perspective.
We
also
discuss
current
design
discovery
strategies
for
inhibitors,
providing
insight
into
potential
inhibitors.
Journal of Medicinal Chemistry,
Journal Year:
2022,
Volume and Issue:
65(3), P. 2388 - 2408
Published: Jan. 4, 2022
Bromodomain-containing
protein
4
(BRD4)
is
an
emerging
epigenetic
drug
target
for
intractable
inflammatory
disorders.
The
lack
of
highly
selective
inhibitors
among
BRD4
family
members
has
stalled
the
collective
understanding
this
critical
system
and
progress
toward
clinical
development
effective
therapeutics.
Here
we
report
discovery
a
potent
bromodomain
1
(BD1)-selective
inhibitor
ZL0590
(52)
targeting
unique,
previously
unreported
binding
site,
while
exhibiting
significant
anti-inflammatory
activities
in
vitro
vivo.
X-ray
crystal
structural
analysis
complex
with
human
BD1
associated
mutagenesis
study
illustrate
first-in-class
nonacetylated
lysine
(KAc)
site
located
at
helix
αB
αC
interface
that
contains
important
residues
(e.g.,
Glu151)
not
commonly
shared
other
spatially
distinct
from
classic
KAc
recognition
pocket.
This
new
finding
facilitates
further
elucidation
biology
underpinning
specificity
its
protein–protein
interaction
partners.