Journal of the American Chemical Society,
Journal Year:
2019,
Volume and Issue:
141(46), P. 18370 - 18374
Published: Sept. 30, 2019
Induction
of
protein
degradation
is
emerging
as
a
powerful
strategy
to
modulate
functions
and
alter
cellular
signaling
pathways.
Proteolysis-targeting
chimeras
(PROTACs)
have
been
used
degrade
range
diverse
proteins
in
vitro
vivo.
Here
we
present
type
photo-caged
PROTACs
(pc-PROTACs)
induce
activity
with
light.
Photo-removable
blocking
groups
were
added
degrader
Brd4,
the
resulting
molecule
pc-PROTAC1
showed
potent
live
cells
only
after
light
irradiation.
Furthermore,
this
efficiently
degraded
Brd4
induced
expected
phenotypic
changes
zebrafish.
Additionally,
approach
was
successfully
applied
construct
pc-PROTAC3
BTK.
Thus,
general
established
augment
chemists'
toolbox
study
disease-relevant
targets.
Annual Review of Biochemistry,
Journal Year:
2017,
Volume and Issue:
86(1), P. 129 - 157
Published: April 4, 2017
Ubiquitin
E3
ligases
control
every
aspect
of
eukaryotic
biology
by
promoting
protein
ubiquitination
and
degradation.
At
the
end
a
three-enzyme
cascade,
ubiquitin
mediate
transfer
from
an
E2
ubiquitin-conjugating
enzyme
to
specific
substrate
proteins.
Early
investigations
E3s
RING
(really
interesting
new
gene)
HECT
(homologous
E6AP
carboxyl
terminus)
types
shed
light
on
their
enzymatic
activities,
general
architectures,
degron-binding
modes.
Recent
studies
have
provided
deeper
mechanistic
insights
into
catalysis,
activation,
regulation.
In
this
review,
we
summarize
current
progress
in
structure-function
as
well
exciting
discoveries
novel
classes
diverse
recognition
mechanisms.
Our
increased
understanding
ligase
function
regulation
has
rationale
for
developing
E3-targeting
therapeutics
treatment
human
diseases.
Science,
Journal Year:
2017,
Volume and Issue:
356(6336)
Published: March 17, 2017
An
old
cancer
drug's
degrading
new
look
Typically,
drugs
that
help
only
a
small
number
of
patients
in
clinical
trials
are
not
pursued.
This
might
change
future
world
precision
medicine,
where
biomarkers
will
match
specific
to
the
most
likely
respond.
Han
et
al.
identified
mechanism
action
drug
called
indisulam,
sulfonamide
tested
previously
with
solid
tumors.
Indisulam
and
related
sulfonamides
killed
cells
by
disrupting
precursor
mRNA
splicing.
The
targeted
RNA
splicing
factor
for
degradation
“gluing”
it
CUL4-DCAF15
ubiquitin
ligase.
Experiments
cell
lines
suggest
these
should
focus
on
leukemias
lymphomas
high
DCAF15
expression
levels.
Science
,
this
issue
p.
eaal3755
Drug Discovery Today Technologies,
Journal Year:
2019,
Volume and Issue:
31, P. 15 - 27
Published: Feb. 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.
