ACS Chemical Biology,
Год журнала:
2024,
Номер
19(7), С. 1484 - 1494
Опубликована: Июль 3, 2024
Targeted
protein
degradation
has
recently
emerged
as
a
novel
option
in
drug
discovery.
Natural
half-life
is
expected
to
affect
the
efficacy
of
degrading
agents,
but
what
extent
it
influences
target
not
been
systematically
explored.
Using
simple
mathematical
modeling
degradation,
we
find
that
natural
dramatic
effect
on
level
induced
by
degrader
agent
which
can
pose
significant
hurdles
screening
efforts.
Moreover,
show
upon
for
degraders
short-lived
proteins,
agents
stall
synthesis,
such
GSPT1
and
generally
cytotoxic
compounds,
deceptively
appear
protein-degrading
agents.
This
exemplified
disappearance
proteins
MCL1
MDM2
treatment
with
doxorubicin.
These
findings
have
implications
selection
well
type
control
experiments
required
conclude
works
bona
fide
targeted
degrader.
Journal of Chemical Information and Modeling,
Год журнала:
2023,
Номер
63(17), С. 5408 - 5432
Опубликована: Авг. 21, 2023
The
therapeutic
approach
of
targeted
protein
degradation
(TPD)
is
gaining
momentum
due
to
its
potentially
superior
effects
compared
with
inhibition.
Recent
advancements
in
the
biotech
and
pharmaceutical
sectors
have
led
development
compounds
that
are
currently
human
trials,
some
showing
promising
clinical
results.
However,
use
computational
tools
TPD
still
limited,
as
it
has
distinct
characteristics
traditional
drug
design
methods.
involves
creating
a
ternary
structure
(protein-degrader-ligase)
responsible
for
biological
function,
such
ubiquitination
subsequent
proteasomal
degradation,
which
depends
on
spatial
orientation
interest
(POI)
relative
E2-loaded
ubiquitin.
Modeling
this
necessitates
unique
blend
initially
developed
small
molecules
(e.g.,
docking)
biologics
protein-protein
interaction
modeling).
Additionally,
degrader
molecules,
particularly
heterobifunctional
degraders,
generally
larger
than
conventional
molecule
drugs,
leading
challenges
determining
drug-like
properties
like
solubility
permeability.
Furthermore,
catalytic
nature
makes
occupancy-based
modeling
insufficient.
consists
multiple
interconnected
yet
steps,
POI
binding,
E3
ligase
interactions,
ubiquitination,
along
properties.
A
comprehensive
set
needed
address
dynamic
induced
proximity
complex
implications
ubiquitination.
In
Perspective,
we
discuss
current
state
TPD.
We
start
by
describing
series
steps
involved
process
experimental
methods
used
characterize
them.
Then,
delve
into
detailed
analysis
employed
also
present
an
integrative
proven
successful
impact
project
decisions.
Finally,
examine
future
prospects
areas
greatest
potential
impact.
Journal of the American Chemical Society,
Год журнала:
2023,
Номер
145(13), С. 7218 - 7229
Опубликована: Март 27, 2023
Event-driven
bifunctional
molecules,
typified
by
proteolysis
targeting
chimera
(PROTAC)
technology,
have
been
successfully
applied
in
degrading
many
proteins
of
interest
(POI).
Due
to
the
unique
catalytic
mechanism,
PROTACs
will
induce
multiple
cycles
degradation
until
elimination
target
protein.
Here,
we
propose
a
versatile
"Ligation
scavenging"
approach
terminate
event-driven
for
first
time.
Ligation
scavenging
system
consists
TCO-modified
dendrimer
(PAMAM-G5-TCO)
and
tetrazine-modified
(Tz-PROTACs).
PAMAM-G5-TCO
can
rapidly
scavenge
intracellular
free
via
an
inverse
electron
demand
Diels–Alder
reaction
certain
living
cells.
Thus,
this
work
proposes
flexible
chemical
knockdown
adjust
levels
POI
on-demand
cells,
which
paves
way
controlled
protein
degradation.
Cancers,
Год журнала:
2024,
Номер
16(3), С. 663 - 663
Опубликована: Фев. 4, 2024
Induced
protein
degradation
has
emerged
as
an
innovative
drug
discovery
approach,
complementary
to
the
classical
method
of
suppressing
function.
The
androgen
receptor
signaling
pathway
been
identified
primary
driving
force
in
development
and
progression
lethal
castration-resistant
prostate
cancer.
Since
degraders
function
differently
from
antagonists,
they
hold
promise
overcome
resistance
challenges
faced
by
current
therapeutics.
Proteolysis-targeting
chimeras
(PROTACs),
monomeric
degraders,
hydrophobic
tagging,
molecular
glues,
autophagic
have
demonstrated
their
capability
downregulating
intracellular
concentrations.
potential
these
treat
cancer
is
substantiated
advancement
six
PROTACs
two
into
phase
I
or
II
clinical
trials.
Although
chemical
structures,
vitro
vivo
data,
mechanisms
reviewed,
it
crucial
stay
updated
on
recent
advances
this
field
novel
new
strategies
continue
emerge.
This
review
thus
provides
insight
advancements
paradigm,
offering
overview
progress
made
since
2020.
ACS Chemical Biology,
Год журнала:
2024,
Номер
19(7), С. 1484 - 1494
Опубликована: Июль 3, 2024
Targeted
protein
degradation
has
recently
emerged
as
a
novel
option
in
drug
discovery.
Natural
half-life
is
expected
to
affect
the
efficacy
of
degrading
agents,
but
what
extent
it
influences
target
not
been
systematically
explored.
Using
simple
mathematical
modeling
degradation,
we
find
that
natural
dramatic
effect
on
level
induced
by
degrader
agent
which
can
pose
significant
hurdles
screening
efforts.
Moreover,
show
upon
for
degraders
short-lived
proteins,
agents
stall
synthesis,
such
GSPT1
and
generally
cytotoxic
compounds,
deceptively
appear
protein-degrading
agents.
This
exemplified
disappearance
proteins
MCL1
MDM2
treatment
with
doxorubicin.
These
findings
have
implications
selection
well
type
control
experiments
required
conclude
works
bona
fide
targeted
degrader.
