Programmed cell death is essential for homeostasis but may also contribute to disabling neuronal pathologies. Four genetically distinct mechanisms of cell death are known: apoptosis, autophagy, necrosis, and ferroptosis. Ferroptosis has been found to cause excitotoxic and degenerative damage to neurons. Importantly, Ferrostatin-1 (Fer-1) is a potent inhibitor of ferroptosis and has prevented cell death in in vitro models of Huntington’s disease, periventricular leukomalacia and kidney dysfunction. Following this success, analogs of Fer-1 were created, focusing on optimizing the compound’s stability and solubility thereby making it a more viable therapeutic candidate. This technology is a set of Fer-1 derivatives, one of which, SRS 15-72, was found to have physical properties compatible with pharmaceutical preparation, making it a promising therapeutic candidate for pathologies that include ferroptosis.
Fer-1 prevents glutamate-induced excitotoxicity in rat brain samples, as well as ferroptopic cell death in cancerous tissue and various neurodegenerative disease models including Huntington’s disease. Structure-activity relationship experiments following Fer-1 led to the synthesis of SRS 15-72 which has comparable potency while exhibiting increased stability and solubility in vitro. Altogether, this technology has the potential to be a potent tool in the fight against degenerative diseases involving lipid peroxidation such as amyotrophic lateral sclerosis, Huntington’s disease, and Parkinson’s disease.
Tech Ventures Reference: IR CU14077