Target-directed dynamic combinatorial chemistry (tdDCC) enables identification, as well as optimization of ligands for un(der)explored targets such as the anti-infective target 1-deoxy-D-xylulose-5-phosphate synthase (DXPS). We report the use of tdDCC...
Proteolysis targeting chimera (PROTAC)-mediated protein
degradation
has prompted a radical rethink and is at a crucial stage in driving
a drug discovery transition. To fully harness the potential of this
technology, a growing paradigm toward enriching PROTACs with other
therapeutic modalities has been proposed. Could researchers successfully
combine two modalities to yield
multifunctional
PROTACs
with an expanded profile? In this Perspective, we try to answer this
question. We discuss how this possibility encompasses different approaches,
leading to
multitarget
PROTACs,
light-controllable
PROTACs, PROTAC
conjugates
, and
macrocycle-
and
oligonucleotide-based
PROTACs. This possibility
promises to further enhance PROTAC efficacy and selectivity, minimize
side effects, and hit undruggable targets. While PROTACs have reached
the clinical investigation stage, additional steps must be taken toward
the translational development of
multifunctional
PROTACs.
A deeper and detailed understanding of the most critical challenges
is required to fully exploit these opportunities and decisively enrich
the PROTAC toolbox.
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