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

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.