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Light-induced control of protein destruction by opto-PROTAC

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 uncontro...

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Autores principales: Liu, Jing, Chen, He, Ma, Leina, He, Zhixiang, Wang, Dong, Liu, Yi, Lin, Qian, Zhang, Tinghu, Gray, Nathanael, Kaniskan, H. Ümit, Jin, Jian, Wei, Wenyi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034987/
https://www.ncbi.nlm.nih.gov/pubmed/32128407
http://dx.doi.org/10.1126/sciadv.aay5154
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author Liu, Jing
Chen, He
Ma, Leina
He, Zhixiang
Wang, Dong
Liu, Yi
Lin, Qian
Zhang, Tinghu
Gray, Nathanael
Kaniskan, H. Ümit
Jin, Jian
Wei, Wenyi
author_facet Liu, Jing
Chen, He
Ma, Leina
He, Zhixiang
Wang, Dong
Liu, Yi
Lin, Qian
Zhang, Tinghu
Gray, Nathanael
Kaniskan, H. Ümit
Jin, Jian
Wei, Wenyi
author_sort Liu, Jing
collection PubMed
description 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 degradation of protein targets in a spatiotemporal manner. By adding a photolabile caging group on pomalidomide as a parental compound and two additional PROTACs, dBET1 and dALK, we demonstrated light-inducible protein degradation. These opto-PROTACs display no activities in the dark, while the restricted degradation can be induced at a specific time and rate by ultraviolet A irradiation. Our approach provides a generalizable platform for the development of light-controlled PROTACs and enables PROTAC to be a precision medicine.
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spelling pubmed-70349872020-03-03 Light-induced control of protein destruction by opto-PROTAC Liu, Jing Chen, He Ma, Leina He, Zhixiang Wang, Dong Liu, Yi Lin, Qian Zhang, Tinghu Gray, Nathanael Kaniskan, H. Ümit Jin, Jian Wei, Wenyi Sci Adv Research Articles 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 degradation of protein targets in a spatiotemporal manner. By adding a photolabile caging group on pomalidomide as a parental compound and two additional PROTACs, dBET1 and dALK, we demonstrated light-inducible protein degradation. These opto-PROTACs display no activities in the dark, while the restricted degradation can be induced at a specific time and rate by ultraviolet A irradiation. Our approach provides a generalizable platform for the development of light-controlled PROTACs and enables PROTAC to be a precision medicine. American Association for the Advancement of Science 2020-02-21 /pmc/articles/PMC7034987/ /pubmed/32128407 http://dx.doi.org/10.1126/sciadv.aay5154 Text en Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Liu, Jing
Chen, He
Ma, Leina
He, Zhixiang
Wang, Dong
Liu, Yi
Lin, Qian
Zhang, Tinghu
Gray, Nathanael
Kaniskan, H. Ümit
Jin, Jian
Wei, Wenyi
Light-induced control of protein destruction by opto-PROTAC
title Light-induced control of protein destruction by opto-PROTAC
title_full Light-induced control of protein destruction by opto-PROTAC
title_fullStr Light-induced control of protein destruction by opto-PROTAC
title_full_unstemmed Light-induced control of protein destruction by opto-PROTAC
title_short Light-induced control of protein destruction by opto-PROTAC
title_sort light-induced control of protein destruction by opto-protac
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034987/
https://www.ncbi.nlm.nih.gov/pubmed/32128407
http://dx.doi.org/10.1126/sciadv.aay5154
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