These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
Crews Carreira photoPROTAC manuscript ChemRxiv high resolution.pdf (813.89 kB)
Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable photoPROTACs
Preprints are manuscripts made publicly available before they have been submitted for formal peer review and publication. They might contain new research findings or data. Preprints can be a draft or final version of an author's research but must not have been accepted for publication at the time of submission.
revised on 17.06.2019 and posted on 17.06.2019by Patrick Pfaff, Kusal
T. G. Samarasinghe, Craig M. Crews, Erick Carreira
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
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
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).