Light-induced control of protein destruction by opto-PROTAC.

Jing Liu, He Chen, Leina Ma, Zhixiang He, Dong Wang, Yi Liu, Qian Lin, Tinghu Zhang, Nathanael Gray, H Ümit Kaniskan, Jian Jin, Wenyi Wei

Science advances 2020 Feb

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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. 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).

Citation

Jing Liu, He Chen, Leina Ma, Zhixiang He, Dong Wang, Yi Liu, Qian Lin, Tinghu Zhang, Nathanael Gray, H Ümit Kaniskan, Jian Jin, Wenyi Wei. Light-induced control of protein destruction by opto-PROTAC. Science advances. 2020 Feb;6(8):eaay5154