Advances in light-controllable PROTACs: Design strategies, therapeutic applications and current challenges

Area of Science:

• Biochemistry
• Molecular Biology
• Chemical Biology

Background:

• Light-controllable protein degradation-targeting chimeras (Light-controllable PROTACs) represent a significant advancement in targeted protein degradation.
• These systems utilize photo-responsive moieties to achieve spatiotemporal control over the degradation of disease-related proteins.

Purpose of the Study:

• To systematically review the molecular design principles of light-controllable PROTACs.
• To explore their applications in cancer therapy, particularly for solid tumors.
• To identify future challenges and opportunities for developing next-generation programmable degradation therapies.

Main Methods:

• Integration of photo-responsive moieties (e.g., photo-caging groups, photo-switchable modules) into PROTAC structures.
• Development of reversible ultraviolet and visible light-responsive systems.
• Investigation of alternative stimuli (hypoxia, X-ray irradiation) for PROTAC activation.

Main Results:

• Demonstrated high spatiotemporal resolution and minimal off-target toxicity in vitro.
• Showcased potential for precise degradation of disease-related proteins.
• Highlighted limitations in tissue penetration depth and metabolic stability for light-controlled systems.

Conclusions:

• Light-controllable PROTACs hold significant therapeutic promise, especially for solid tumors, due to their precise control.
• Overcoming challenges like limited tissue penetration is crucial for clinical translation.
• Exploring alternative stimuli-based PROTACs offers a path forward for enhanced therapeutic efficacy.