iScience,
Journal Year:
2024,
Volume and Issue:
27(9), P. 110712 - 110712
Published: Aug. 23, 2024
Small-molecule
drugs
are
effective
and
thus
most
widely
used.
However,
their
applications
limited
by
reliance
on
active
high-affinity
binding
sites,
restricting
target
options.
A
breakthrough
approach
involves
molecular
glues,
a
novel
class
of
small-molecule
compounds
capable
inducing
protein-protein
interactions
(PPIs).
This
opens
avenues
to
conventionally
undruggable
proteins,
overcoming
limitations
seen
in
conventional
drugs.
Molecular
glues
play
key
role
targeted
protein
degradation
(TPD)
techniques,
including
ubiquitin-proteasome
system-based
approaches
such
as
proteolysis
targeting
chimeras
(PROTACs)
glue
degraders
recently
emergent
lysosome
techniques
like
extracellular
proteins
through
the
asialoglycoprotein
receptors
(MoDE-As)
macroautophagy
(MADTACs).
These
enable
an
innovative
strategy
for
prolonged
inhibition
pathology-associated
proteins.
review
provides
overview
them,
emphasizing
clinical
potential
guiding
development
molecular-glue-mediated
TPD
techniques.
Cells,
Journal Year:
2023,
Volume and Issue:
13(1), P. 29 - 29
Published: Dec. 22, 2023
Ubiquitination
is
a
reversible
post-translational
modification
based
on
the
chemical
addition
of
ubiquitin
to
proteins
with
regulatory
effects
various
signaling
pathways.
can
alter
molecular
functions
tagged
substrates
respect
protein
turnover,
biological
activity,
subcellular
localization
or
protein–protein
interaction.
As
result,
wide
variety
cellular
processes
are
under
ubiquitination-mediated
control,
contributing
maintenance
homeostasis.
It
follows
that
dysregulation
ubiquitination
reactions
plays
relevant
role
in
pathogenic
states
human
diseases
such
as
neurodegenerative
diseases,
immune-related
pathologies
and
cancer.
In
recent
decades,
enzymes
ubiquitin–proteasome
system
(UPS),
including
E3
ligases
deubiquitinases
(DUBs),
have
attracted
attention
novel
druggable
targets
for
development
new
anticancer
therapeutic
approaches.
This
perspective
article
summarizes
peculiarities
shared
by
involved
reaction
which,
when
deregulated,
lead
tumorigenesis.
Accordingly,
an
overview
main
pharmacological
interventions
targeting
UPS
clinical
use
still
trials
provided,
also
highlighting
limitations
efficacy
these
Therefore,
attempts
circumvent
drug
resistance
side
well
UPS-related
emerging
technologies
therapeutics
discussed.
Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
67(13), P. 10548 - 10566
Published: June 26, 2024
Developing
therapies
for
the
activated
B-cell
like
(ABC)
subtype
of
diffuse
large
lymphomas
(DLBCL)
remains
an
area
unmet
medical
need.
A
subset
ABC
DLBCL
tumors
is
driven
by
activating
mutations
in
myeloid
differentiation
primary
response
protein
88
(MYD88),
which
lead
to
constitutive
activation
interleukin-1
receptor
associated
kinase
4
(IRAK4)
and
cellular
proliferation.
IRAK4
signaling
its
catalytic
scaffolding
functions,
necessitating
complete
removal
this
escape
mechanisms
therapeutic
suppression.
Herein,
we
describe
identification
characterization
a
dual-functioning
molecule,
KT-413
show
it
efficiently
degrades
transcription
factors
Ikaros
Aiolos.
achieves
concurrent
degradation
these
proteins
functioning
as
both
heterobifunctional
degrader
molecular
glue.
Based
on
demonstrated
activity
safety
preclinical
studies,
phase
1
clinical
trial
lymphomas,
including
MYD88
mutant
DLBCL,
currently
underway.
Expert Opinion on Drug Discovery,
Journal Year:
2024,
Volume and Issue:
19(4), P. 433 - 449
Published: Jan. 19, 2024
Introduction
Molecular
Glue
Degraders
(MGDs)
is
a
concept
that
refers
to
class
of
compounds
facilitate
the
interaction
between
two
proteins
or
molecules
within
cell.
These
act
as
bridge
enhances
specific
Protein-Protein
Interactions
(PPIs).
Over
past
decade,
this
technology
has
gained
attention
potential
strategy
target
were
traditionally
considered
undruggable
using
small
molecules.
Journal of Medicinal Chemistry,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 24, 2025
The
discovery
of
molecular
glues
has
made
significant
strides,
unlocking
new
avenues
for
targeted
protein
degradation
as
a
therapeutic
strategy,
thereby
expanding
the
scope
drug
into
territories
previously
considered
undruggable.
Pioneering
molecules
like
thalidomide
and
its
derivatives
have
paved
way
development
small
that
can
induce
specific
by
hijacking
cellular
ubiquitin–proteasome
system.
Recent
advancements
focused
on
range
E3
ligases
target
proteins
be
modulated
glues.
Structural
elucidation
ligase
in
complex
with
glue
interest,
combined
computational
modeling,
facilitates
understanding
underlying
mechanisms
how
degradation.
By
leveraging
these
tools,
next
generation
are
expected
to
offer
unprecedented
opportunities
combating
wide
diseases,
including
cancer,
autoimmune
disorders,
neurodegenerative
conditions.
Cancers,
Journal Year:
2022,
Volume and Issue:
14(22), P. 5698 - 5698
Published: Nov. 20, 2022
High
rates
of
recurrence
and
distant
metastasis
are
a
foremost
challenge
in
the
management
adenoid
cystic
carcinoma
(ACC),
occurring
approximately
40%
all
ACC
patients.
Despite
morbidity
mortality
resulting
from
recurrent/metastatic
(R/M)
disease,
there
no
FDA-approved
systemic
agents
for
these
In
this
review,
we
summarize
pertinent
pathophysiology
its
implications
different
treatment
regimens
R/M
ACC.
We
review
evidence
most
widely
used
—
cytotoxic
chemotherapy
tyrosine
kinase
inhibitors
(TKIs)
targeting
VEGFR
addition
to
immune
checkpoint
non-TKI
biologic
agents.
Exciting
emerging
targets
ACC,
including
Notch
signaling,
stemness,
PRMT5,
Axl,
also
discussed.
Lastly,
local
therapies
small-volume
lung
disease
patients
with
oligometastatic
specifically
pulmonary
metastasectomy
stereotactic
body
radiation
therapy
(SBRT).
Future
development
targeted
molecular
which
exploit
underlying
biology
may
yield
novel
therapeutic
options
improve
clinical
outcomes
Trends in Pharmacological Sciences,
Journal Year:
2023,
Volume and Issue:
44(11), P. 786 - 801
Published: Sept. 29, 2023
Targeted
protein
degradation
(TPD)
is
an
emerging
modality
for
research
and
therapeutics.
Most
TPD
approaches
harness
cellular
ubiquitin-dependent
proteolytic
pathways.
Proteolysis-targeting
chimeras
(PROTACs)
molecular
glue
(MG)
degraders
(MGDs)
represent
the
most
advanced
approaches,
with
some
already
used
in
clinical
settings.
Despite
these
advances,
still
faces
many
challenges,
pertaining
to
both
development
of
effective,
selective,
tissue-penetrant
understanding
their
mode
action.
In
this
review,
we
focus
on
progress
made
addressing
challenges.
particular,
discuss
utility
application
recent
proteomic
as
indispensable
tools
enable
insights
into
degrader
development,
including
target
engagement,
selectivity,
efficacy,
safety,
