2020
DOI: 10.1126/sciadv.aay5154
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Light-induced control of protein destruction by opto-PROTAC

Abstract: By hijacking endogenous E3 ligase to degrade protein targets via the ubiquitin-proteasome system, PROTACs (PRoteolysis TArgeting Chimeras) provide a new strategy to inhibit protein targets that were regarded as undruggable before. However, the catalytic nature of PROTAC potentially leads to uncontrolled degradation that causes systemic toxicity issues, limiting the application of PROTAC in the clinic. Here, we introduce a light-inducible switch on PROTACs, thereafter termed as opto-PROTAC, to enable the degrad… Show more

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Cited by 168 publications
(198 citation statements)
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(85 reference statements)
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“…Indeed, the tissuespecific expression of E3 ligases used in PROTACs will need to be ascertained as well as the impact that drafting an endogenous E3 ligase for therapeutic help might have on the system. Further exciting developments include combining optogenetics with protein degrader strategies such as Opto-PROTACs, as this could provide added control over the timing and induction of protein degradation (424).…”
Section: Discussionmentioning
confidence: 99%
“…Indeed, the tissuespecific expression of E3 ligases used in PROTACs will need to be ascertained as well as the impact that drafting an endogenous E3 ligase for therapeutic help might have on the system. Further exciting developments include combining optogenetics with protein degrader strategies such as Opto-PROTACs, as this could provide added control over the timing and induction of protein degradation (424).…”
Section: Discussionmentioning
confidence: 99%
“… 264 Specifically, PROTAC consists two functional parts, connected by a chemical linker: a “warhead” (normally a small molecule) that binds to a targeted protein, and a ligand which is recognized by a cullin-RING ligase, leading to degradation of the target protein. 264 As such, PROTAC provides an effective approach to target these undruggable proteins, 265 267 such as transcriptional factor SOX2 (Fig. 7 , approach 7).…”
Section: Summary and Future Perspectivesmentioning
confidence: 99%
“…Given its fundamental role in embryonic development 3 and epithelial tissue homeostasis, 188 associated cytotoxicity of SOX2 targeting should be an important issue to consider. A newly developed light-inducible switch on PROTAC, which triggers the degradation of any given targeted proteins restrictedly at desirable site and time window by ultraviolet irradiation, 267 , 268 should be incorporated in the SOX2-targeting strategy of PROTAC to overcome the potential side-effects.…”
Section: Summary and Future Perspectivesmentioning
confidence: 99%
“…In light-controllable PROTACs, a photo-removable group is attached to either a POI ligand or E3 ligand or linker. This photo-removable group is detached from the PROTAC upon light irradiation converting it to an active PROTAC [ 23 , 30 , 31 ]. The design and mechanisms of action of homo-PROTACs and light-controllable PROTACs are illustrated in Fig.…”
Section: Advantages Of Using Protacs Over Other Approaches To Inhibitmentioning
confidence: 99%