Abstract
Proteolysis
targeting
chimeras
(PROTACs)
have
emerged
as
a
promising
strategy
for
drug
discovery
and
exploring
protein
functions,
offering
revolutionary
therapeutic
modality.
Currently,
the
predominant
approach
to
PROTACs
mainly
relies
on
an
empirical
design–synthesis–evaluation
process
involving
numerous
cycles
of
labor‐intensive
synthesis‐purification
bioassay
data
collection.
Therefore,
development
innovative
methods
expedite
PROTAC
synthesis
exploration
chemical
space
remains
highly
desired.
Here,
direct‐to‐biology
is
reported
streamline
libraries
plates,
enabling
seamless
transfer
reaction
products
cell‐based
bioassays
without
need
additional
purification.
By
integrating
amide
coupling
light‐induced
primary
amines
o‐nitrobenzyl
alcohols
cyclization
(PANAC)
photoclick
chemistry
into
plate‐based
synthetic
process,
this
produces
with
high
efficiency
structural
diversity.
Moreover,
by
employing
platform
screening,
we
smoothly
found
potent
effectively
inhibit
triple‐negative
breast
cancer
(TNBC)
cell
growth
induce
rapid,
selective
targeted
degradation
cyclin‐dependent
kinase
9
(CDK9).
The
study
introduces
versatile
assembling
followed
direct
biological
evaluation.
This
provides
opportunity
high‐throughput
libraries,
thereby
enhancing
accelerating
PROTACs.
Chemical Society Reviews,
Год журнала:
2024,
Номер
53(10), С. 4838 - 4861
Опубликована: Янв. 1, 2024
In
this
review
we
highlight
how
the
synthesis
of
degraders
has
evolved
in
recent
years,
particular
application
high-throughput
chemistry
and
screening
approaches
such
as
D2B
DEL
technologies
to
expedite
discovery
timelines.
RSC Medicinal Chemistry,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 7, 2024
PROTACs
are
an
emerging
therapeutic
approach
towards
targeted
protein
degradation.
This
article
examines
the
leading
examples
of
this
modality
that
in
clinical
development
through
prism
their
physicochemical
properties.
Royal Society of Chemistry eBooks,
Год журнала:
2025,
Номер
unknown, С. 134 - 156
Опубликована: Фев. 21, 2025
Targeted
protein
degradation
(TPD)
provides
new
therapeutic
opportunities
beyond
traditional
inhibitors.
TPD
relies
on
the
ability
to
induce
proximity
between
an
E3
ligase
and
target
of
interest,
harnessing
ubiquitin
proteasome
system
ubiquitylate
degrade
target.
This
can
be
induced
by
either
monofunctional
ligands
(molecular
glues)
or
bifunctional
molecules
that
tether
ligases
together.
DNA
encoded
libraries
(DELs)
provide
rapid
access
diverse
chemical
space
for
ligand
discovery
and,
their
design,
facilitate
development
both
molecular
glues
degraders.
Expert Opinion on Therapeutic Patents,
Год журнала:
2025,
Номер
unknown, С. 1 - 42
Опубликована: Янв. 21, 2025
The
von
Hippel-Lindau
(VHL)
E3
ubiquitin
ligase
has
seen
extensive
research
due
to
its
involvement
in
the
proteasome
system
and
role
as
a
tumor
suppressor
within
hypoxia
signaling
pathway.
VHL
become
an
attractive
target
for
proteolysis
targeting
chimeras
(PROTACs),
bifunctional
molecules
that
can
induce
degradation
of
neo-substrate
proteins.
development
inhibitors
PROTACs
rapid
since
disclosure
first
non-peptidic
ligand
(2012).
Due
demand
more
diverse
sophisticated
ligands
be
applied
PROTACs,
number
patents
disclosed
risen
significantly
past
5
years.
Herein,
wide
range
modifications
have
been
patented
2019
is
covered.
Specifically,
any
new
or
unique
chemical
modification
established
will
discussed.
space
continues
expand
patent
literature.
There
are
exciting
enhance
physiochemical
properties
other
alterations
improve
affinity
itself.
Further
optimization
no
doubt
lead
VHL-based
therapies
clinical
candidates.
The Journal of Organic Chemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 2, 2025
Ultra
high-throughput
chemistry
carried
out
in
1536-well
plates
is
increasingly
utilized
for
reaction
optimization
protocols
and
direct-to-biology
(D2B)
platforms,
where
nanomolar
quantities
of
the
final
product
are
directly
assessed
biochemical
or
cellular
activity
without
purification.
As
their
popularity
increases,
it
crucial
that
synthesis
these
molecules
reliable
reproducible.
Research
our
laboratories
has
identified
several
nuances
amide
couplings
when
performed
on
nanoscale
result
poor
translation
from
to
batch-scale
reactions.
This
case
study
presents
a
coupling
synthesize
700
PROTAC
molecules,
which
range
factors
success
nanoscale,
despite
having
no
influence
conversion
batch.
work
guide
chemists
consider
working
importance
drawing
conclusions
synthesis.
Abstract
The
Hit
to
Lead
(H2L)
process
is
an
integral
part
of
contemporary
drug
discovery,
encompassing
the
optimisation
validated
structures
into
molecules.
High
quality
leads
build
confidence,
through
activity
and
property
profiles
as
well
preliminary
biological
data,
which
might
include
validating
pharmacologic
hypotheses
along
way,
indicating
that
further
investment
in
structure(s)
target
would
be
worthwhile.
Leads
have
line
sight
a
development
candidate
bring
understanding
what
priorities
Optimisation
should
address.
In
this
set
best
practices,
we
detail
essential
criteria
characterise
good
lead,
establishing
SAR
from
analogues
assessing
DMPK
indicators,
selectivity
early
safety
parameters.
We
highlight
importance
identifying
liabilities
lead
series
demonstrating
each
can
individually
modulated
whilst
maintaining
on
potency.
make
case
for
having
physicochemical
properties
critical
parameters
how
ligand
efficiency
metrics
enable
this.
Then
go
over
general
tactics
used
convert
hits
series.
These
steps
that,
when
performed
early,
increase
chance
success
such
deconstructive
SAR,
pharmacophore
bioactive
conformation
determination
scaffold
optimisation.
Finally,
suggest
decision‐making
substantiate
confidence
or,
importantly,
making
recommendation
cease
work
