Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable photoPROTACs
2019
Off-target 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-target 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 because 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 vastly useful in experimental
probing of biological signaling pathways – especially those crucial for oncogenic signal transduction.
Additionally, this strategy may be suitable for therapeutic implementation in a
wide variety of disease phenotypes. By enabling reversible activation and
deactivation of protein degradation, photoPROTACs
offer advantages over conventional photocaging strategies that irreversibly release
active agents.
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