bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Sept. 18, 2024
Abstract
Constraining
proximity-based
drugs,
such
as
proteolysis-targeting
chimeras
(PROTACs),
into
its
bioactive
conformation
can
significantly
impact
their
selectivity
and
potency.
However,
traditional
methods
for
achieving
this
often
involve
complex
time-consuming
synthetic
procedures.
Here,
we
introduced
an
alternative
approach
by
demonstrating
DNA-templated
spatially
controlled
PROTACs
(DTACs),
which
leverage
the
programmability
of
nucleic-acid
based
self-assembly
efficient
synthesis,
providing
precise
control
over
inhibitors’
spacing
orientation.
The
resulting
constructs
revealed
distance-
orientation-dependent
degradation
potency
CyclinD1-CDK4/6
protein
in
cancer
cells.
Notably,
optimal
construct
DTAC-V1
demonstrated
unprecedented
synchronous
entire
complex.
This
resulted
effective
cell
cycle
arrest
G1
phase,
further
therapeutic
studies
showed
potent
anti-tumor
effects
compared
to
inhibitors
alone.
These
findings
present
a
novel
framework
design,
offering
critical
insights
that
may
inform
development
other
proximity-induced
modalities.
Journal of the American Chemical Society,
Journal Year:
2025,
Volume and Issue:
unknown
Published: April 19, 2025
Deubiquitinase-targeting
chimera
(DUBTAC)
has
emerged
as
a
promising
technology
for
targeted
protein
stabilization
(TPS)
by
harnessing
deubiquitinases
(DUBs)
to
remove
polyubiquitin
chains
from
target
proteins.
Despite
the
presence
of
over
100
human
DUBs,
only
OTUB1
and
USP7
have
been
utilized
in
development
DUBTAC.
Hence,
there
is
an
urgent
need
harness
additional
DUBs
expand
DUBTAC
arsenal.
In
this
work,
we
demonstrate
first
time
that
USP1
deubiquitinase,
which
overexpressed
several
cancers,
can
be
leveraged
TPS.
We
report
novel
USP1-recruiting
DUBTACs
utilizing
noncovalent
small-molecule
inhibitor
USP1.
First,
generated
USP1-based
CFTR
DUBTAC,
MS5310,
effectively
stabilized
more
potent
than
previously
reported
DUBTACs.
Next,
developed
first-in-class
UTX
DUBTACs,
including
MS7131,
JMJD3.
Notably,
MS7131
tumor
suppressor
concentration-
time-dependent
manner,
while
sparing
oncoprotein
JMJD3,
despite
it
retaining
inhibition
Furthermore,
induced
was
dependent
on
engagement
both
UTX.
Consequently,
but
not
parent
or
inhibitor,
reduced
histone
H3
lysine
27
trimethylation
significantly
suppressed
proliferation
clonogenicity
cancer
cells.
Overall,
study
highlights
harnessed
development.
Moreover,
valuable
chemical
tool,
investigation
UTX's
distinct
functions.
This
advancement
paves
way
leveraging
treatment
related
diseases.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Sept. 18, 2024
Abstract
Constraining
proximity-based
drugs,
such
as
proteolysis-targeting
chimeras
(PROTACs),
into
its
bioactive
conformation
can
significantly
impact
their
selectivity
and
potency.
However,
traditional
methods
for
achieving
this
often
involve
complex
time-consuming
synthetic
procedures.
Here,
we
introduced
an
alternative
approach
by
demonstrating
DNA-templated
spatially
controlled
PROTACs
(DTACs),
which
leverage
the
programmability
of
nucleic-acid
based
self-assembly
efficient
synthesis,
providing
precise
control
over
inhibitors’
spacing
orientation.
The
resulting
constructs
revealed
distance-
orientation-dependent
degradation
potency
CyclinD1-CDK4/6
protein
in
cancer
cells.
Notably,
optimal
construct
DTAC-V1
demonstrated
unprecedented
synchronous
entire
complex.
This
resulted
effective
cell
cycle
arrest
G1
phase,
further
therapeutic
studies
showed
potent
anti-tumor
effects
compared
to
inhibitors
alone.
These
findings
present
a
novel
framework
design,
offering
critical
insights
that
may
inform
development
other
proximity-induced
modalities.
