Related Experiment Video
Updated: Jun 30, 2026
Photodynamic Therapy with Blended Conducting Polymer/Fullerene Nanoparticle Photosensitizers
Published on: October 28, 2015
Photo-Activated PROTACs for Targeted BRD4 Degradation and Synergistic Photodynamic Therapy in Bladder Cancer
Ke Wang1, Mingzhu Zhang1, Cheng Huang1
1College of Chemistry and Materials Science, Jiangsu Key Laboratory of Bio-functional Materials, Jiangsu Collaborative Innovation Centre of Biomedical Functional Materials, Key Laboratory of Applied Photochemistry, Nanjing Normal University, Nanjing 210023, China.
Abstract:
Proteolysis-targeting chimera (PROTAC) drugs rely on the formation of a ternary complex consisting of the target protein, the drug, and a ubiquitin-protein ligase (E3 ubiquitin ligase). However, some cancer patients may not exhibit sufficient expression of both the target protein and the E3 ligase in tumor tissues, leading to potential off-target effects when treated with conventional PROTACs. In this study, we have developed a photoactivated PROTAC strategy that employs the photosensitizer monosubstituted amino phthalocyanine (ZnPc) and the bromine domain protein 4 (BRD4) ligand (JQ1) as core components. A series of highly active compounds were designed and the most effective and safe candidate (ZnPc-O3-JQ1), was identified. Upon activation by light, ZnPc-O3-JQ1 generates reactive oxygen species (ROS) that degrade BRD4. The degradation of BRD4 results in downregulation of hypoxia-inducible factor-1α (HIF-1α), thereby counteracting the treatment resistance induced by tumor hypoxia during photodynamic therapy (PDT). Furthermore, to mitigate oxidative stress caused by ROS, cells upregulate cystine/glutamate antiporter system (Xc- system, SLC7A11) to enhance glutathione (GSH) synthesis. However, downregulation of HIF-1α inhibits GSH synthesis by inhibiting glutamate-cysteine ligase (GCL, the key enzyme in the de novo synthesis of GSH), disrupting the antioxidant defense system. This photo-PROTAC strategy enables a mutually synergistic effect between PDT and PROTAC, providing a new avenue for the design of safer and more efficient PROTAC drugs, photosensitizers, and combination therapies.
Insights
This study introduces a novel photoactivated Proteolysis-Targeting Chimera (PROTAC) that uses light to degrade BRD4, overcoming limitations of conventional PROTACs and enhancing cancer therapy by synergizing photodynamic therapy (PDT) with targeted protein degradation.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
- Photodynamic Therapy
- Drug Discovery
Background:
- Conventional Proteolysis-Targeting Chimera (PROTAC) drugs require sufficient target protein and E3 ubiquitin ligase expression, which is often lacking in cancer patients.
- This limitation can lead to potential off-target effects and reduced therapeutic efficacy.
- Tumor hypoxia contributes to treatment resistance, particularly during photodynamic therapy (PDT).
Purpose of the Study:
- To develop a photoactivated PROTAC strategy to overcome limitations of conventional PROTACs.
- To investigate the synergistic effects between PDT and PROTAC-mediated degradation.
- To design safer and more effective PROTAC drugs and combination therapies for cancer treatment.
Main Methods:
- Development of a photoactivated PROTAC using monosubstituted amino phthalocyanine (ZnPc) as a photosensitizer and JQ1 as a BRD4 ligand.
- Design and synthesis of a series of active compounds, identifying ZnPc-O3-JQ1 as the lead candidate.
- Evaluation of light-activated reactive oxygen species (ROS) generation for targeted BRD4 degradation and its downstream effects on HIF-1α and glutathione (GSH) synthesis.
Main Results:
- The photoactivated PROTAC ZnPc-O3-JQ1 effectively degrades BRD4 upon light activation.
- BRD4 degradation leads to downregulation of hypoxia-inducible factor-1α (HIF-1α), counteracting hypoxia-induced resistance during PDT.
- The strategy disrupts the cellular antioxidant defense system by inhibiting GSH synthesis, creating a synergistic effect between PDT and PROTAC.
Conclusions:
- Photoactivated PROTACs offer a promising alternative to conventional PROTACs, especially when target or E3 ligase expression is insufficient.
- This approach establishes a mutually synergistic relationship between PDT and PROTAC, enhancing therapeutic outcomes.
- The developed strategy provides a novel platform for designing advanced PROTAC drugs, photosensitizers, and combination therapies for improved cancer treatment.
More Related Videos
11:04An In-House-Built and Light-Emitting-Diode-Based Photodynamic Therapy Device for Enhancing Verteporfin Cytotoxicity in a 2D Cell Culture Model
Published on: January 13, 2023
07:24Development of an Innovative LED-based Illumination Device for In Vitro Application of Photodynamic Therapy with Rose Bengal
Published on: September 12, 2025
