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Crews Carreira photoPROTAC manuscript ChemRxiv high resolution.pdf (813.89 kB)
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Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable photoPROTACs

preprint
revised on 17.06.2019 and posted on 17.06.2019 by Patrick Pfaff, Kusal T. G. Samarasinghe, Craig M. Crews, Erick Carreira
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.

Funding

C.M.C. gratefully acknowledges support from the NIH (R35 CA197589). C.M.C. is a shareholder in and consultant to Arvinas, Inc., which partially supported this work. P.P. acknowledges a fellowship of the Stipendienfonds Schweizerische Chemische Industrie (SSCI).

History

Email Address of Submitting Author

carreira@org.chem.ethz.ch

Institution

ETH Zürich

Country

Switzerland

ORCID For Submitting Author

0000-0003-1472-490X

Declaration of Conflict of Interest

C.M.C. is a shareholder in and consultant to Arvinas, Inc.

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