PDTAC: Targeted Photodegradation of GPX4 Triggers Ferroptosis and Potent Antitumor Immunity.
Sijin LiuXi ZhaoSufang ShuiBiao WangYingxian CuiSuwei DongTairan YuwenGuoquan LiuPublished in: Journal of medicinal chemistry (2022)
Targeted degradation of proteins, especially those regarded as undruggable or difficult to drug, attracts wide attention to develop novel therapeutic strategies. Glutathione peroxidase 4 (GPX4), the key enzyme regulating ferroptosis, is currently a target with just covalent inhibitors. Here, we developed a targeted photolysis approach and achieved efficient degradation of GPX4. The photodegradation-targeting chimeras (PDTACs) were synthesized by conjugating a clinically approved photosensitizer (verteporfin) to noninhibitory GPX4-targeting peptides. These chimeras selectively degraded the target protein in both cell lysates and living cells upon red-light irradiation. The targeted photolysis of GPX4 resulted in dominant ferroptotic cell death in malignant cancer cells. Moreover, the dying cells resulting from the PDTACs exhibited potent immunogenicity in vitro and efficiently elicited antitumor immunity in vivo. Our approach therefore provides a novel method to induce GPX4 dysfunction based on noncovalent binding and specifically trigger immunogenic ferroptosis, which may boost the application of ferroptosis in cancer immunotherapy.
Keyphrases
- cell death
- cancer therapy
- cell cycle arrest
- living cells
- drug delivery
- fluorescent probe
- photodynamic therapy
- palliative care
- working memory
- emergency department
- amino acid
- nitric oxide
- binding protein
- anti inflammatory
- radiation therapy
- single molecule
- cell proliferation
- small molecule
- pi k akt
- bone marrow
- dna binding
- electronic health record