Abstract
Proteolysis‐targeting
chimeras
(PROTACs),
an
emerging
paradigm‐shifting
technology,
hijacks
the
ubiquitin‐proteasome
system
for
targeted
protein
degradation.
PROTACs
induce
ternary
complexes
between
E3
ligase
and
POI,
this
induced
proximity
leads
to
polyUb
chain
formation
on
substrates
eventual
proteasomal‐mediated
POI
have
shown
great
therapeutic
potential
by
degrading
many
disease‐causing
proteins,
such
as
androgen
receptor
BRD4.
The
PROTAC
technology
has
advanced
significantly
in
last
two
decades,
with
repertoire
of
targets
increased
tremendously.
Herein,
we
describe
recent
developments
focusing
mechanistic
kinetic
studies,
pharmacokinetic
study,
spatiotemporal
control
PROTACs,
covalent
resistance
new
ligands.
Drug Discovery Today Technologies,
Год журнала:
2019,
Номер
31, С. 15 - 27
Опубликована: Фев. 13, 2019
The
majority
of
currently
used
therapeutics
are
small
molecule-based
and
utilize
occupancy-driven
pharmacology
as
the
mode
action
(MOA),
in
which
protein
function
is
modulated
via
temporary
inhibition.
New
modalities
that
operate
using
alternative
MOAs
essential
for
tapping
into
"undruggable"
proteome.
PROteolysis
Targeting
Chimera
(PROTAC)
technology
provides
an
attractive
new
approach
utilizes
event-driven
MOA.
Small
heterobifunctional
PROTACs
modulate
target
levels
by
hijacking
ubiquitin-proteasome
system
to
induce
degradation
target.
Here,
we
address
important
milestones
development
PROTAC
technology,
well
emphasize
key
findings
from
this
previous
year
highlight
future
directions
promising
drug
discovery
modality.
Signal Transduction and Targeted Therapy,
Год журнала:
2019,
Номер
4(1)
Опубликована: Дек. 24, 2019
Although
many
kinds
of
therapies
are
applied
in
the
clinic,
drug-resistance
is
a
major
and
unavoidable
problem.
Another
disturbing
statistic
limited
number
drug
targets,
which
presently
only
20-25%
all
protein
targets
that
currently
being
studied.
Moreover,
focus
current
explorations
their
enzymatic
functions,
ignores
functions
from
scaffold
moiety.
As
promising
appealing
technology,
PROteolysis
TArgeting
Chimeras
(PROTACs)
have
attracted
great
attention
both
academia
industry
for
finding
available
approaches
to
solve
above
problems.
PROTACs
regulate
function
by
degrading
target
proteins
instead
inhibiting
them,
providing
more
sensitivity
drug-resistant
greater
chance
affect
nonenzymatic
functions.
been
proven
show
better
selectivity
compared
classic
inhibitors.
can
be
described
as
chemical
knockdown
approach
with
rapidity
reversibility,
presents
new
different
biology
other
gene
editing
tools
avoiding
misinterpretations
arise
potential
genetic
compensation
and/or
spontaneous
mutations.
PRTOACs
widely
explored
throughout
world
outperformed
not
cancer
diseases,
but
also
immune
disorders,
viral
infections
neurodegenerative
diseases.
present
very
powerful
crossing
hurdles
discovery
tool
development
biology,
efforts
needed
gain
get
deeper
insight
into
efficacy
safety
clinic.
More
binders
E3
ligases
applicable
developing
waiting
exploration.
Signal Transduction and Targeted Therapy,
Год журнала:
2022,
Номер
7(1)
Опубликована: Апрель 4, 2022
Abstract
Traditional
drug
discovery
mainly
focuses
on
direct
regulation
of
protein
activity.
The
development
and
application
activity
modulators,
particularly
inhibitors,
has
been
the
mainstream
in
development.
In
recent
years,
PROteolysis
TArgeting
Chimeras
(PROTAC)
technology
emerged
as
one
most
promising
approaches
to
remove
specific
disease-associated
proteins
by
exploiting
cells’
own
destruction
machinery.
addition
PROTAC,
many
different
targeted
degradation
(TPD)
strategies
including,
but
not
limited
to,
molecular
glue,
Lysosome-Targeting
Chimaera
(LYTAC),
Antibody-based
PROTAC
(AbTAC),
are
emerging.
These
technologies
have
only
greatly
expanded
scope
TPD,
also
provided
fresh
insights
into
discovery.
Here,
we
summarize
advances
major
TPD
technologies,
discuss
their
potential
applications,
hope
provide
a
prime
for
both
biologists
chemists
who
interested
this
vibrant
field.
Journal of the American Chemical Society,
Год журнала:
2021,
Номер
143(2), С. 593 - 598
Опубликована: Янв. 4, 2021
Targeted
protein
degradation
has
emerged
as
a
new
paradigm
to
manipulate
cellular
proteostasis.
Proteolysis-targeting
chimeras
(PROTACs)
are
bifunctional
small
molecules
that
recruit
an
E3
ligase
target
of
interest,
promoting
its
ubiquitination
and
subsequent
degradation.
Here,
we
report
the
development
antibody-based
PROTACs
(AbTACs),
fully
recombinant
bispecific
antibodies
membrane-bound
ligases
for
cell-surface
proteins.
We
show
AbTAC
can
induce
lysosomal
programmed
death-ligand
1
by
recruitment
RNF43.
AbTACs
represent
archetype
within
PROTAC
field
proteins
with
biological
molecules.
