Medicinal Research Reviews,
Journal Year:
2022,
Volume and Issue:
42(3), P. 1280 - 1342
Published: Jan. 10, 2022
Abstract
Proteolysis
targeting
chimaeras
(PROTACs)
is
a
cutting
edge
and
rapidly
growing
technique
for
new
drug
discovery
development.
Currently,
the
largest
challenge
in
molecular
design
development
of
PROTACs
efficient
identification
potent
drug‐like
degraders.
This
review
aims
to
comprehensively
summarize
analyse
state‐of‐the‐art
methods
strategies
PROTACs.
We
provide
detailed
illustration
general
principles
tactics
designing
PROTACs,
highlight
representative
case
studies,
discuss
advantages
limitations
these
strategies.
Particularly,
structure‐based
rational
PROTAC
emerging
types
(e.g.,
homo‐PROTACs,
multitargeting
photo‐control
PROTAC‐based
conjugates)
will
be
focused
on.
Chemical Society Reviews,
Journal Year:
2020,
Volume and Issue:
50(2), P. 1305 - 1353
Published: Dec. 10, 2020
Antibody–drug
conjugates
(ADCs)
harness
the
highly
specific
targeting
capabilities
of
an
antibody
to
deliver
a
cytotoxic
payload
cell
types.
This
review
summarises
advances
made
in
construction
homogenous
ADCs.
Journal of the American Chemical Society,
Journal Year:
2021,
Volume and Issue:
143(19), P. 7380 - 7387
Published: May 10, 2021
PROTACs
(proteolysis
targeting
chimeras)
are
an
emerging
class
of
promising
therapeutic
modalities
that
degrade
intracellular
protein
targets
by
hijacking
the
cellular
ubiquitin–proteasome
system.
However,
potential
toxicity
in
normal
cells
due
to
off-tissue
on-target
degradation
effect
limits
their
clinical
applications.
Precise
control
a
PROTAC's
activity
tissue-selective
manner
could
minimize
toxicity/side-effects.
To
this
end,
we
developed
cancer
cell
selective
delivery
strategy
for
conjugating
folate
group
ligand
VHL
E3
ubiquitin
ligase,
achieve
targeted
proteins
interest
(POIs)
versus
noncancerous
cells.
We
show
our
folate-PROTACs,
including
BRD
PROTAC
(folate-ARV-771),
MEK
(folate-MS432),
and
ALK
(folate-MS99),
capable
degrading
BRDs,
MEKs,
ALK,
respectively,
receptor-dependent
This
design
provides
generalizable
platform
POIs
Angewandte Chemie International Edition,
Journal Year:
2021,
Volume and Issue:
60(43), P. 23299 - 23305
Published: July 9, 2021
Development
of
proteolysis
targeting
chimeras
(PROTACs)
is
emerging
as
a
promising
strategy
for
targeted
protein
degradation.
However,
the
drug
development
using
heterobifunctional
PROTAC
molecules
generally
limited
by
poor
membrane
permeability,
low
in
vivo
efficacy
and
indiscriminate
distribution.
Herein
an
aptamer-PROTAC
conjugation
approach
was
developed
novel
to
improve
tumor-specific
ability
antitumor
potency
conventional
PROTACs.
As
proof
concept,
first
conjugate
(APC)
designed
conjugating
BET-targeting
nucleic
acid
aptamer
AS1411
(AS)
via
cleavable
linker.
Compared
with
unmodified
BET
PROTAC,
molecule
(APR)
showed
improved
tumor
MCF-7
xenograft
model,
leading
enhanced
degradation
decreased
toxicity.
Thus,
APC
may
pave
way
design
PROTACs
have
broad
applications
PROTAC-based
drugs.
Journal of Biological Chemistry,
Journal Year:
2021,
Volume and Issue:
296, P. 100647 - 100647
Published: Jan. 1, 2021
Of
late,
targeted
protein
degradation
(TPD)
has
surfaced
as
a
novel
and
innovative
chemical
tool
therapeutic
modality.
By
co-opting
pathways,
TPD
facilitates
complete
removal
of
the
molecules
from
within
or
outside
cell.
While
pioneering
Proteolysis-Targeting
Chimera
(PROTAC)
technology
molecular
glues
hijack
ubiquitin-proteasome
system,
newer
modalities
co-opt
autophagy
endo-lysosomal
pathway.
Using
this
mechanism,
is
posited
to
largely
expand
druggable
space
far
beyond
small-molecule
inhibitors.
In
review,
we
discuss
major
advances
in
TPD,
highlight
our
current
understanding,
explore
outstanding
questions
field.
