Ferrostatins for therapeutic control of reactive oxygen species in excitotoxic and degenerative diseases

This technology is a set of ferrostatin-1 (Fer-1) derivatives optimized for enhanced stability and solubility to serve as therapeutic candidates against pathologies driven by ferroptosis.

Unmet Need: Stable and soluble ferroptosis inhibitors for degenerative diseases

Ferroptosis is a form of iron-dependent programmed cell death characterized by the accumulation of lipid reactive oxygen species (ROS). While the small molecule ferrostatin-1 (Fer-1) has been discovered as a inhibitor of ferroptosis, it lacks metabolic and microsomal stability which limits its efficacy in physiological settings. There is currently a lack of stable ferroptosis inhibitors in development that have the drug-like properties, such as high bioavailability and water solubility, required to effectively protect tissues and organs in in vivo models of degenerative diseases.

The Technology: Ferrostatin derivatives with enhanced stability and solubility

This technology consists of a series of ferrostatin-1 (Fer-1) derivatives designed through structure-activity relationship (SAR) analysis to improve the drug-like properties of the original Fer-1 molecule. The synthesized lead analog, SRS 15-72, demonstrates significantly improved microsomal stability and calculated solubility (cLogP) while maintaining potent inhibition of oxidative cell death. By overcoming the metabolic limitations of earlier probes, these optimized derivatives offer a viable pathway for in vivo testing and potential therapeutic development to protect neural and somatic cells from ferroptosis-induced injury.

This technology has been validated in vitro through potency, stability, and bioavailability testing of the synthesized analogs in multiple disease and tissue models.

Applications:

• Small molecule therapeutic for degenerative disease
• Prophylaxis for neurodegeneration
• Probe for studying ferroptosis and neurodegeneration
• Method of modulating ferroptotic activity
• Method of modulating cell life spans
• Method of modulating iron metabolism
• New approach to antioxidant therapy

Advantages:

• Microsomal stability and solubility confirmed in vitro
• Based on compound with demonstrated in vitro effectiveness
• Inhibits ferroptosis, a cell-death mechanism involved in various neurodegenerative diseases.

Lead Inventor:

Brent Stockwell, PhD

Patent Information:

Patent Issued (US10,259,775)

Related Publication:

• Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR. “Ferroptosis: an iron-dependent form of nonapoptotic cell death.” Cell. 2012 May 25; 149(5): 1060 1072.

• Yang WS, Stockwell BR. “Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells.” Chem Biol. 2008 Mar 24; 15(3): 234-245.

• Dolma S, Lessnick SL, Hahn WC, Stockwell BR. “Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells.” Cancer Cell. 2003 Mar; 3(3): 285-296.

Tech Ventures Reference:

• IR CU14077, CU17132

• Licensing Contact: Joan Martinez