Enzymatic inhibition has proven to
be a successful modality for
the development of many small-molecule drugs. In recent years, small-molecule-induced
protein degradation has emerged as an orthogonal therapeutic strategy
that has the potential to expand the druggable target space. Focal
adhesion kinase (Fak) is a key player in tumor invasion and metastasis,
acting simultaneously as a kinase and a scaffold for several signaling
proteins. While previous efforts to modulate Fak activity were limited
to kinase inhibitors with low success in clinical studies, protein
degradation offers a possibility to simultaneously block Fak’s
kinase signaling and scaffolding capabilities. Here, we report the
development of a selective and potent Fak degrader, PROTAC-3, which outperforms a clinical candidate, defactinib, with respect
to Fak activation as well as Fak-mediated cell migration and invasion.
These results underline the potential that PROTACs offer in expanding
the druggable space and controlling protein functions that are not
easily addressed by traditional small-molecule therapeutics.
Off-tissue effects
are persistent issues of modern inhibition-based
therapies. By merging the strategies of photopharmacology and small-molecule
degraders, we introduce a novel concept for persistent spatiotemporal
control of induced protein degradation that potentially prevents off-tissue
toxicity. Building on the successful principle of bifunctional all-small-molecule
Proteolysis Targeting Chimeras (PROTACs), we designed photoswitchable
PROTACs (photoPROTACs) by including ortho-F4-azobenzene linkers between both warhead ligands. This
highly bistable yet photoswitchable structural component leads to
reversible control over the topological distance between both ligands.
The azo-cis-isomer is observed to
be inactive because the distance defined by the linker is prohibitively
short to permit complex formation between the protein binding partners.
By contrast, the azo-trans-isomer
is active since it can engage both protein partners to form the necessary
and productive ternary complex. Importantly, due to the bistable nature
of the ortho-F4-azobenzene moiety employed,
the photostationary state of the photoPROTAC is persistent,
with no need for continuous irradiation. This technique offers reversible
on/off switching of protein degradation that is compatible with an
intracellular environment and, therefore, could be useful in experimental
exploration of biological signaling pathways—such as those
crucial for oncogenic signal transduction. Additionally, this strategy
may be suitable for therapeutic intervention to address a variety
of diseases. By enabling reversible activation and deactivation of
protein degradation, photoPROTACs offer advantages over
conventional photocaging strategies that irreversibly release active
agents.
Highlights d TRAFTACs are heterobifunctional chimeric oligos d Transcription factors are recruited to the double-stranded DNA of the chimeric TRAFTACs d TRAFTACs are generalizable d Brachyury-TRAFTAC induces no tail phenotype in zebrafish embryos
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