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Development of visible-light-activatable photocaged PROTACs
Weizhi Weng1, Gang Xue1, Zhengying Pan1
1State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055, China.
Abstract:
Photocaged proteolysis-targeting chimeras (PROTACs), which employ light as a stimulus to control protein degradation, have recently garnered considerable attention as both powerful chemical tools and a promising therapeutic strategy. However, the poor penetration depth of traditionally used ultraviolet light and the deficiency of alternative caging positions have restricted their applications in biological systems. By installing a diverse array of photocaged groups, with excitation wavelengths ranging from 365 nm to 405 nm, onto different positions of cereblon (CRBN) and Von Hippel-Lindau (VHL)-recruiting Brd4 degraders, we conducted the first comprehensive study on visible-light-activatable photocaged PROTACs to the best of our knowledge. We found the A2, A4 and B3 positions to be most effective at regulating the activity of the degraders, and to provide the resulting molecules (9-12 and 17) as potent visible-light-controlled degraders in live cells.
Insights
Researchers developed visible-light-activatable photocaged proteolysis-targeting chimeras (PROTACs) for precise control over protein degradation. This advancement overcomes limitations of ultraviolet light, enabling new applications in biological research and therapeutics.
Area of Science:
- Chemical biology
- Molecular pharmacology
- Drug discovery
Background:
- Photocaged proteolysis-targeting chimeras (PROTACs) offer light-inducible protein degradation.
- Current limitations include poor UV light penetration and lack of diverse caging positions.
- Visible-light activation is desirable for deeper tissue penetration and broader biological applications.
Purpose of the Study:
- To develop and characterize visible-light-activatable photocaged PROTACs.
- To investigate the impact of different photocaging positions on PROTAC activity.
- To identify potent visible-light-controlled PROTACs for use in live cells.
Main Methods:
- Synthesis of photocaged PROTACs utilizing photocaged groups with excitation wavelengths from 365 nm to 405 nm.
- Modification of cereblon (CRBN) and Von Hippel-Lindau (VHL)-recruiting Brd4 degraders at various positions.
- Evaluation of photocaged PROTAC activity and control in live-cell degradation assays.
Main Results:
- Identified specific positions (A2, A4, B3) on PROTACs as most effective for activity regulation.
- Developed potent visible-light-controlled PROTAC molecules (compounds 9-12 and 17).
- Demonstrated effective protein degradation in live cells using visible light.
Conclusions:
- Visible-light-activatable photocaged PROTACs represent a significant advancement over UV-light-dependent systems.
- Strategic placement of photocaged groups is crucial for optimizing PROTAC function.
- These novel PROTACs offer enhanced control for biological applications and therapeutic strategies.
