Compounds for modulating ferroptosis and treating excitotoxic disorders

This technology describes a class of chemical compounds that specifically modulate cellular ferroptosis to treat a range of excitotoxic disorders.

Unmet Need: Alternative pathways for cell death inhibition

Regulated cell death, known as apoptosis, is a critical process in normal tissue function. However, the deregulation of this process can result in progression of various excitotoxic disorders including neurodegenerative disorders, cancer, and diabetes. Many of these excitotoxic disorders are resistant to traditional modulators of apoptosis. As such, there is a need to identify parallel modes of cell death that may enable the treatment and prevention of associated diseases. Ferroptosis is an iron-dependent type of programmed cell death that is distinct from other well-characterized cell death pathways. As such, manipulation of ferroptosis may provide a therapeutic target for the treatment of a wide range of diseases.

The Technology: Ferroptosis inhibitors to treat excitotoxic disorders

This technology describes a class of small molecules that specifically inhibit cellular ferroptosis. The ferroptosis inhibitors were identified through screening assays and further analogs were synthesized to increase the effectiveness and pharmacological properties of the small molecules. By modulating ferroptosis as an alternative to apoptosis, this technology has the potential to treat a wide range of excitotoxic disorders including cancers and neurodegenerative diseases.

The identified ferroptosis inhibitors have been demonstrated to modulate ferroptosis in tumorigenic cells and rat hippocampal slice cultures.

Applications:

• Prevention of cell death
• Inhibition of non-standard cell death pathways
• Reducing reactive oxygen species in cells
• Treating or ameliorating the effects of a neurodegenerative disease
• Specific targeting of tumorigenic cancer cells
• Treatment of other excitotoxic disorders

Advantages:

• Distinct pathway for treatment that may avoid resistance faced in traditional approaches
• Applications in multiple high-volume disease areas, including neurodegenerative diseases and cancer
• Inexpensive to produce
• Flexible approach due to multiple small molecule options

Lead Inventor:

Brent R. Stockwell, Ph.D.

Patent Information:

Patent Status

Related Publications:

• Zhang Y, Tan H, Daniels JD, Zandkarimi F, Liu H, Brown LM, Uchida K, O’Connor OA, Stockwell BR. “Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model” Cell Chem Biol. 2019 May 16; 26(5): 623-633.

• Youssef LA, Rebbaa A, Pampou S, Weisberg SP, Stockwell BR, Hod EA, Spitalnik SL. “Increased erythrophagocytosis induces ferroptosis in red pulp macrophages in a mouse model of transfusion” Blood. 2018 Jun 7; 131(23): 2581-2593.

• Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K, Rosenberg PA, Lo DC, Weinberg JM, Linkermann A, Stockwell BR. “Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models” J Am Chem Soc. 2014 Mar 26; 136(12): 4551-4556.

Tech Ventures Reference:

• IR CU12192

• Licensing Contact: Beth Kauderer