Journal of Medicinal Chemistry,
Год журнала:
2023,
Номер
66(7), С. 5041 - 5060
Опубликована: Март 22, 2023
DCAF1
is
a
substrate
receptor
of
two
distinct
E3
ligases
(CRL4DCAF1
and
EDVP),
plays
critical
physiological
role
in
protein
degradation,
considered
drug
target
for
various
cancers.
Antagonists
could
be
used
toward
the
development
therapeutics
cancers
viral
treatments.
We
WDR
domain
to
screen
114-billion-compound
DNA
encoded
library
(DEL)
identified
candidate
compounds
using
similarity
search
machine
learning.
This
led
discovery
compound
(Z1391232269)
with
an
SPR
KD
11
μM.
Structure-guided
hit
optimization
OICR-8268
(26e)
38
nM
cellular
engagement
EC50
10
μM
as
measured
by
thermal
shift
assay
(CETSA).
excellent
tool
enable
next-generation
ligands
cancer
therapeutics,
further
investigation
functions
cells,
DCAF1-based
PROTACs.
Chemical Society Reviews,
Год журнала:
2022,
Номер
51(12), С. 5214 - 5236
Опубликована: Янв. 1, 2022
Proteolysis-targeting
chimeras
(PROTACs)
are
heterobifunctional
molecules
consisting
of
one
ligand
that
binds
to
a
protein
interest
(POI)
and
another
can
recruit
an
E3
ubiquitin
ligase.
The
chemically-induced
proximity
between
the
POI
ligase
results
in
ubiquitination
subsequent
degradation
by
ubiquitin-proteasome
system
(UPS).
event-driven
mechanism
action
(MOA)
PROTACs
offers
several
advantages
compared
traditional
occupancy-driven
small
molecule
inhibitors,
such
as
catalytic
nature,
reduced
dosing
frequency,
more
potent
longer-lasting
effect,
added
layer
selectivity
reduce
potential
toxicity,
efficacy
face
drug-resistance
mechanisms,
targeting
nonenzymatic
functions,
expanded
target
space.
Here,
we
highlight
important
milestones
briefly
discuss
lessons
learned
about
targeted
(TPD)
recent
years
conjecture
on
efforts
still
needed
expand
toolbox
for
PROTAC
discovery
ultimately
provide
promising
therapeutics.
Journal of Biological Chemistry,
Год журнала:
2021,
Номер
296, С. 100647 - 100647
Опубликована: Янв. 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.
Abstract
Proteolysis-targeting
chimeras
(PROTACs)
are
engineered
techniques
for
targeted
protein
degradation.
A
bifunctional
PROTAC
molecule
with
two
covalently-linked
ligands
recruits
target
and
E3
ubiquitin
ligase
together
to
trigger
proteasomal
degradation
of
by
the
ubiquitin-proteasome
system.
has
emerged
as
a
promising
approach
therapy
in
various
diseases,
particularly
cancers.
In
this
review,
we
introduce
principle
development
technology,
well
advantages
PROTACs
over
traditional
anti-cancer
therapies.
Moreover,
summarize
application
targeting
critical
oncoproteins,
provide
guidelines
molecular
design
discuss
challenges
PROTACs.
RSC Chemical Biology,
Год журнала:
2021,
Номер
2(3), С. 725 - 742
Опубликована: Янв. 1, 2021
With
the
discovery
of
PROteolysis
TArgeting
Chimeras
(PROTACs)
twenty
years
ago,
targeted
protein
degradation
(TPD)
has
changed
landscape
drug
development.
