Molecules,
Год журнала:
2024,
Номер
29(22), С. 5334 - 5334
Опубликована: Ноя. 13, 2024
Neoplastic
cells
are
characterized
by
uncontrolled
cell
divisions
caused
cycle
dysregulation.
Key
regulatory
proteins
governing
the
transition
from
G1
to
S
phase
CDK4
and
CDK6
kinases,
which
controlled
D-type
cyclins.
The
CDK4/6
kinases
enable
use
of
these
as
targets
for
anticancer
therapy
because
they
prevent
growth
development
malignant
inhibiting
their
activity.
This
paper
surveys
clinical
trial
results
concerning
palbociclib,
first
in-class
FDA-approved
drug
hormone-dependent
breast
cancer.
It
discusses
therapeutic
applications
in
cancer
well
solid
tumors
hematopoietic
malignancies.
Additionally,
presents
an
analysis
palbociclib
resistance
acquired
during
explores
new
approaches,
such
modifications
that
enhance
its
desired
activity
or
open
up
possibilities
(PROTACs).
Expert Opinion on Drug Discovery,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 5, 2025
Targeted
protein
degradation
(TPD)
is
a
cutting-edge
technology
that
provides
new
avenues
for
drug
discovery
and
development.
PROteolysis
TArgeting
Chimeras
(PROTACs)
are
the
most
established
advanced
TPD
strategy,
enabling
selective
of
disease-associated
'undruggable'
proteins
interest
(POIs)
by
leveraging
cell's
natural
machinery.
To
confirm
PROTAC-induced
proximity
drives
degradation,
target
validation
ternary
complex
formation
must
be
thoroughly
assessed.
In
this
perspective,
authors
detail
some
widely
used
in
silico,
structural,
vitro,
cellulo
methods
to
validate
PROTAC
engagement
formation.
Additionally,
they
discuss
growing
use
PROTACs
as
chemical
probes
novel
identification
validation.
Target
essential
approach,
ongoing
studies
should
prioritize
confirming
using
assays
conducted
under
physiologically
relevant
cellular
conditions.
The
believe
proteomics
analyses
among
valuable
tools
elucidating
mechanism,
selectivity,
outcomes
PROTACs.
They
also
remain
optimistic
about
future
development
their
engagement.
While
rapidly
advancing,
it
still
holds
vast
opportunities
exploration,
offering
significant
potential
further
both
biological
research
drive
drugs.
Journal of Biological Chemistry,
Год журнала:
2025,
Номер
unknown, С. 108520 - 108520
Опубликована: Апрель 1, 2025
Proteasome
substrate
receptor
hRpn13
is
a
promising
target
for
cancer
therapy.
PROTACs
induce
apoptosis
by
targeting
the
proteolytic
product
hRpn13Pru,
which
contains
an
intact
ubiquitin-
and
proteasome-binding
Pru
domain.
We
generated
PROTAC
series
based
on
hRpn13Pru-targeting
XL5
varying
linker
that
connects
it
to
warhead
against
VHL-based
ubiquitin
E3
ligase
machinery.
Among
eight
tested
derivatives,
XL5-VHL-7
with
-(CH2)5-
alkyl
promoted
hRpn13Pru
degradation
induced
cellular
2-fold
improved
potency
compared
original
PROTAC.
By
using
this
slight
chemical
modifications
in
region,
we
were
able
evaluate
efficacy
of
structural
modeling
molecular
dynamics
refining
PROTACs.
Overall,
found
experimental
data
correlated
predictions
modeling.
Moreover,
could
observe
hRpn13:PROTAC:VHL
complexes
2D
NMR
support
stronger
affinity
Our
further
indicate
higher
within
VHL
complex
present
than
alone.
Altogether,
develop
increased
optimizing
demonstrate
current
benefit
limitations
including
aid
optimization.
Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 25, 2024
Inhibition
of
estrogen
receptor
alpha
(ERα)
signaling
is
an
established
therapeutic
approach
for
the
treatment
ER-positive
(ER+)
breast
cancers,
but
new
strategies
are
urgently
needed
to
overcome
clinical
resistance.
In
present
study,
we
describe
discovery
and
extensive
evaluation
ERD-12310A
as
exceptionally
potent
orally
efficacious
PROTAC
degrader
ERα.
achieved
a
DC
Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
67(21), С. 19010 - 19037
Опубликована: Ноя. 1, 2024
Despite
the
development
of
highly
effective
therapies
for
treatment
estrogen
receptor
α
(ERα)-positive
human
breast
cancer,
clinical
resistance
to
current
requires
novel
therapeutic
strategies.
Herein,
we
report
discovery
ERD-1233
as
a
potent
and
orally
efficacious
ERα
degrader
designed
using
PROTAC
technology.
was
developed
based
on
Lasofoxifene
ER
binding
moiety
cereblon
ligand
through
extensive
optimization
linker.
potently
effectively
reduces
protein
in
vitro
achieves
excellent
oral
bioavailability
mice
rats.
Oral
administration
ER+
tumors
tumor
regression
wild-type
MCF-7
xenograft
model
strong
growth
inhibition
ESR1Y537S
mutated
mice.
Our
data
demonstrate
that
is
promising
evaluation
new
therapy
cancer.
Biomedicines,
Год журнала:
2024,
Номер
12(12), С. 2700 - 2700
Опубликована: Ноя. 26, 2024
Estrogen
receptor
α
(ERα)
drives
two
out
of
three
breast
cancers
and
therefore
ERα
is
a
major
therapeutic
target
for
ER-positive
cancer
patients.
Drugs
that
inhibit
activity
or
block
estrogen
synthesis
in
the
body
are
currently
being
used
clinic
to
treat
have
been
quite
successful
controlling
progression
majority
However,
often
becomes
resistant
these
endocrine
therapies,
leading
endocrine-resistant
metastatic
cancer,
very
aggressive
leads
death.
Recent
large-scale
genomic
studies
revealed
series
activating
somatic
mutations
gene
(ESR1)
Of
these,
Y537S
D538G
found
at
much
higher
rate
patients
with
cancer.
Remarkably,
produce
an
transcriptional
than
wild
type
absence
estradiol,
traditional
therapy
has
poor
efficacy
against
ER
mutants.
Therefore,
development
new
drugs
mutants
unmet
clinical
need
This
review
summarizes
recent
preclinical
trials
targeting
mutant
Molecules,
Год журнала:
2024,
Номер
29(22), С. 5334 - 5334
Опубликована: Ноя. 13, 2024
Neoplastic
cells
are
characterized
by
uncontrolled
cell
divisions
caused
cycle
dysregulation.
Key
regulatory
proteins
governing
the
transition
from
G1
to
S
phase
CDK4
and
CDK6
kinases,
which
controlled
D-type
cyclins.
The
CDK4/6
kinases
enable
use
of
these
as
targets
for
anticancer
therapy
because
they
prevent
growth
development
malignant
inhibiting
their
activity.
This
paper
surveys
clinical
trial
results
concerning
palbociclib,
first
in-class
FDA-approved
drug
hormone-dependent
breast
cancer.
It
discusses
therapeutic
applications
in
cancer
well
solid
tumors
hematopoietic
malignancies.
Additionally,
presents
an
analysis
palbociclib
resistance
acquired
during
explores
new
approaches,
such
modifications
that
enhance
its
desired
activity
or
open
up
possibilities
(PROTACs).
