Novel Ferroptosis Inducers To Treat Cancer

Project ID: D2022-15

Background

Ferroptosis is a non-apoptotic cell death mechanism impelled by unrestrained accumulation of iron-dependent cellular reactive oxygen (ROS) species leading to membrane lipid peroxidation resulting from intra-cellular antioxidant depletion. Clinical application of ferroptosis agents/drugs has been elusive due to off-target effects leading to drug toxicity 11. Improved understanding of protein targets and the mechanism of action of ferroptosis agents can contribute to their successful clinical application. Thus, there is a need for novel nontoxic and highly selective ferroptosis agents.

Invention Description

        Researchers at the University of Toledo developed a new class of ferroptosis inducers called CETZOLEs. Structure-activity relationship studies of these molecules led to the discovery of highly potent CETZOLE analogues. They were confirmed to be typical ferroptosis agents that induce cell death through ROS accumulation by cell rescue and flow cytometry experiments. It induces ferroptosis more selectively in mesenchymal cancer cells like HOP-62, NCI-H522, UACC-62 and A498, as opposed to epithelial cancer cells like HCT-116, HeLa and MCF7, which are less sensitive.

Applications

• Cancer treatment

Advantages

• Effective at nanomolar to low micromolar concentrations
• Particularly effective on mesenchymal cells similar to cancer stem cells responsible for tumor metastasis
• Efficient synthesis amenable to process chemistry with potential to develop a potent chemotherapeutic agent capable of overcoming drug resistance.

Lead Inventor:            Viranga Tillekeratne Ph.D., Department of Medicinal and Biological Chemistry

Publication:                CETZOLE and CETZOLE Analogs as Highly Potent Ferroptotic Agents: Their Target Protein Identification Using Covalent/Affinity Probes. Manuscript in preparation.