Photo-Activated PROTACs for Targeted BRD4 Degradation and Synergistic Photodynamic Therapy in Bladder Cancer

作者：Ke Wang, Mingzhu Zhang, Cheng Huang, Jishuang Zhang, Yinan Hua, Xinlu Qin, Yongming Deng, Shaohua Wei, Lin Zhou · 发表于：Molecular Pharmaceutics · 年份：2025 · DOI：10.1021/acs.molpharmaceut.5c00271 · 被引用次数：8 · 研究领域：Protein Degradation and Inhibitors、Ubiquitin and proteasome pathways、Peptidase Inhibition and Analysis

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-O 3 -JQ1), was identified. Upon activation by light, ZnPc-O 3 -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, providin...