This technology is the development and use of GPX4 inhibitors to activate ferroptosis for the treatment of cancer.
Metastatic cancers undergo epithelial-to-mesenchymal transition (EMT), increasing tumor cell motility and enabling distant invasion. EMT makes cancer cells more reliant on glutathione peroxidase 4 (GPX4), which prevents lipid peroxidation in membranes. Lipid peroxidation triggers ferroptosis, a tumor-suppressive form of regulated cell death enhanced by GPX4 inhibition. However, targeting GPX4 is difficult due to its flat active site and similarity to other peroxidases. These constraints limit current GPX4 inhibitors as effective therapeutic compounds for cancer treatment and as tools to study ferroptosis in physiological and disease states.
This technology describes the development of potent and specific GPX4 inhibitors for cancer treatment. From high-throughput screening hits, structure-based drug design, and structure-activity studies, four generations of structurally distinct analogs have been developed. QW-852 is the most potent and specific compound that can preferentially induce ferroptosis in drug-tolerant cancers. As such, these compounds can potentially be used to better study GPX4 biology and be utilized for GPX4-targeted therapies.
This technology was tested in human HT-1080 fibrosarcoma cells.
Patent Pending (WO/2024/073560)
IR CU20261, CU21144, CU23170
Licensing Contact: Joan Martinez