ZX703: A Small-Molecule Degrader of GPX4 Inducing Ferroptosis in Human Cancer Cells.
Mengdie HuXiaomei LiLin WangYanping ZhangYujie SunHui HuaHuina LiuTing CaiDongsheng ZhuQiuping XiangPublished in: ACS medicinal chemistry letters (2024)
Ferroptosis is a novel form of oxidative cell death triggered by iron-dependent lipid peroxidation. The induction of ferroptosis presents an attractive therapeutic strategy for human diseases, such as prostate cancer and breast cancer. Herein, we describe our design, synthesis, and biological evaluation of endogenous glutathione peroxidase 4 (GPX4) degraders using the proteolysis targeting chimera (PROTAC) approach with the aim of inducing ferroptosis in cancer cells. Our efforts led to the discovery of compound 5i (ZX703), which significantly degraded GPX4 through the ubiquitin-proteasome and the autophagy-lysosome pathways in a dose- and time-dependent manner. Moreover, 5i was found to induce the accumulation of lipid reactive oxygen species (ROS) in HT1080 cells, thereby inducing ferroptosis. This study provides an attractive intervention strategy for ferroptosis-related diseases.
Keyphrases
- cell death
- cell cycle arrest
- small molecule
- prostate cancer
- endothelial cells
- reactive oxygen species
- induced apoptosis
- induced pluripotent stem cells
- pluripotent stem cells
- nitric oxide
- radical prostatectomy
- dna damage
- drug delivery
- oxidative stress
- cell proliferation
- protein protein
- signaling pathway
- single molecule
- living cells
- single cell
- young adults
- iron deficiency