Journal of Pharmaceutical and Biomedical Analysis,
Год журнала:
2024,
Номер
249, С. 116348 - 116348
Опубликована: Июль 9, 2024
Chemically
induced,
targeted
protein
degradation
with
proteolysis
targeting
chimeras
(PROTACs)
has
shown
to
be
a
promising
pharmacological
strategy
circumvent
the
poor
"druggability"
of
intracellular
targets.
However,
favorable
pharmacology
comes
complex
molecular
properties
limiting
oral
bioavailability
these
drugs.
To
foster
translation
PROTACs
into
clinics
it
is
high
importance
establish
sensitive
bioanalytical
methods
that
enable
assessment
absorption,
bioavailability,
and
disposition
after
dosing.
In
this
study,
two
highly
LC-MS/MS
(LLOQ
=
0.5
ng/mL)
were
developed
validated
for
quantification
bavdeglutamide
(ARV-110)
vepdegestrant
(ARV-471)
in
rat
plasma.
Plasma
samples
processed
by
precipitation
separated
on
C18
column
over
gradient
acetonitrile
water
0.1
%
formic
acid.
Selected
reaction
monitoring
positive
ESI
mode
was
applied
quantify
ARV-110
ARV-471.
Both
showed
linearity,
accuracy,
precision
as
well
matrix
effects
carry-over
within
predefined
acceptance
criteria.
High
stability
compounds
plasma
demonstrated
at
long-term
storage
seven
weeks
-20
°C,
three
freeze-thaw
cycles,
up
20
min
room
temperature,
extracts
autosampler.
The
concentration-time
curves
intravenous
intraduodenal
bolus
single-dose
administrations
rats
could
successfully
quantified
clinically
relevant
doses
per
body
weight.
assays
presented
work
application
broad
spectrum
vivo
studies
elucidate
PROTACs.
ACS Central Science,
Год журнала:
2023,
Номер
9(7), С. 1269 - 1284
Опубликована: Июль 14, 2023
Molecular
proximity
orchestrates
biological
function,
and
blocking
existing
proximities
is
an
established
therapeutic
strategy.
By
contrast,
strengthening
or
creating
neoproximity
with
chemistry
enables
modulation
of
processes
high
selectivity
has
the
potential
to
substantially
expand
target
space.
A
plethora
proximity-based
modalities
proteins
via
diverse
approaches
have
recently
emerged,
opening
opportunities
for
biopharmaceutical
innovation.
This
Outlook
outlines
mechanisms
molecules
based
on
induced
proximity,
including
protein
degraders,
blockers,
stabilizers,
inducers
post-translational
modifications,
agents
cell
therapy,
discusses
challenges
that
field
must
address
mature
unlock
translation
in
biology
medicine.
Chemical Society Reviews,
Год журнала:
2024,
Номер
53(4), С. 2099 - 2210
Опубликована: Янв. 1, 2024
Recent
tactical
applications
of
prodrugs
as
effective
tools
in
drug
discovery
and
development
to
resolve
issues
associated
with
delivery
lead
candidates
are
reviewed
a
reflection
the
approval
53
during
2012–2022.
Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
67(15), С. 13106 - 13116
Опубликована: Июль 30, 2024
Achieving
oral
bioavailability
with
Proteolysis
Targeting
Chimeras
(PROTACs)
is
a
key
challenge.
Here,
we
report
the
in
vivo
pharmacokinetic
properties
mouse,
rat,
and
dog
of
four
clinical
PROTACs
compare
an
internally
derived
data
set.
We
use
NMR
to
determine
3D
molecular
conformations
structural
preorganization
free
solution,
introduce
new
experimental
descriptors,
solvent-exposed
H-bond
donors
(eHBD),
acceptors
(eHBA).
derive
upper
limit
eHBD
≤
2
for
apolar
environments
show
greater
tolerance
other
(eHBA,
polarity,
lipophilicity,
weight)
than
Rule-of-5
compliant
drugs.
Within
set
structurally
related
PROTACs,
that
examples
>
have
much
lower
those
2.
summarize
our
findings
as
"Rule-of-oral-PROTACs"
order
assist
medicinal
chemists
achieve
this
challenging
space.
Drug Discovery Today,
Год журнала:
2024,
Номер
29(4), С. 103917 - 103917
Опубликована: Фев. 14, 2024
A
principal
challenge
in
the
discovery
of
proteolysis
targeting
chimeras
(PROTACs)
as
oral
medications
is
their
bioavailability.
To
facilitate
drug
design,
it
therefore
essential
to
identify
chemical
space
where
orally
bioavailable
PROTACs
are
more
likely
be
situated.
this
aim,
we
extracted
structure-bioavailability
insights
from
published
data
using
traditional
2D
descriptors,
thereby
shedding
light
on
potential
and
limitations
design
tools.
Subsequently,
describe
cutting-edge
experimental,
computational
hybrid
strategies
based
3D
which
show
promise
for
enhancing
probability
discovering
with
high
Proteolysis-targeting
chimeras
(PROTACs)
represent
a
transformative
advancement
in
drug
discovery,
offering
method
to
degrade
specific
intracellular
proteins.
Unlike
traditional
inhibitors,
PROTACs
are
bifunctional
molecules
that
target
proteins
for
elimination,
enabling
the
potential
treatment
of
previously
"undruggable"
This
concept,
pioneered
by
Crews
and
his
team,
introduced
use
small
link
protein
an
E3
ubiquitin
ligase,
inducing
ubiquitination
subsequent
degradation
protein.
By
promoting
rather
than
merely
inhibiting
function,
present
novel
therapeutic
strategy
with
enhanced
specificity
effectiveness,
especially
areas
such
as
cancer
neurodegenerative
diseases.
Since
their
initial
field
PROTAC
research
has
rapidly
expanded
numerous
now
designed
wide
range
disease-relevant
The
substantial
research,
investment,
collaboration
across
academia
pharmaceutical
industry
reflect
growing
interest
PROTACs.
Review
discusses
journey
from
discovery
clinical
trials,
highlighting
advancements
challenges.
Additionally,
recent
developments
fluorescent
photogenic
PROTACs,
used
real-time
tracking
degradation,
presented,
showcasing
evolving
targeted
therapy.
Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
67(7), С. 5351 - 5372
Опубликована: Март 26, 2024
CBP/p300
are
critical
transcriptional
coactivators
of
the
androgen
receptor
(AR)
and
promising
cancer
therapeutic
targets.
Herein,
we
report
discovery
highly
potent,
selective,
orally
bioavailable
degraders
using
PROTAC
technology
with
CBPD-409
being
most
compound.
induces
robust
degradation
DC50
0.2–0.4
nM
displays
strong
antiproliferative
effects
IC50
1.2–2.0
in
VCaP,
LNCaP,
22Rv1
AR+
prostate
cell
lines.
It
has
a
favorable
pharmacokinetic
profile
achieves
50%
oral
bioavailability
mice.
A
single
administration
at
1
mg/kg
>95%
depletion
proteins
VCaP
tumor
tissue.
exhibits
growth
inhibition
is
much
more
potent
efficacious
than
two
inhibitors
CCS1477
GNE-049
AR
antagonist
Enzalutamide.
degrader
for
further
extensive
evaluations
treatment
advanced
other
types
human
cancers.
